1,2,4-triazine-4-amine derivatives

ABSTRACT

According to the invention there is provided a compound of formula A1 which may be useful in the treatment of a condition or disorder ameliorated by the inhibition of the A 1 -A 2b  or, particularly, the A 2a  receptor wherein the compound of formula A1 has the structure, wherein, A represents Cy 1  or Het A ; Cy 1  represents a 5- to 14-membered aromatic, fully saturated or partially unsaturated carbocylic ring system comprising one, two or three rings, which Cy 1  group is optionally substituted by one or more R 4a  substituents; Het A  represents a 5- to 14-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, which heterocyclic group may comprise one, two or three rings and which HetA group is optionally substituted by one or more R4b substituents; B represents a Cy 2  or Het B ; Cy 2  represents a 3- to 10-membered aromatic, fully saturated or partially unsaturated carbocyclic ring system comprising one or two rings, which Cy 2  group is optionally substituted by one or more R 4c  substituents; Het B  represents a 3- to 10-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, which heterocyclic group may comprise one or two rings and which Het B  group is optionally substituted by one or more R 4d  substituents.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/976,738, filed Dec. 21, 2015, which is a continuation of U.S. patentapplication Ser. No. 14/322,505, filed Jul. 2, 2014, now U.S. Pat. No.9,249,130, which is a continuation of U.S. patent application Ser. No.13/576,798, filed Oct. 17, 2012, now U.S. Pat. No. 8,809,525, which is a371 of International Application PCT/EP2011/051755, filed on Feb. 7,2011, which claims benefit of priority to U.S. Provisional ApplicationNo. 61/302,060, filed on Feb. 5, 2010; and U.S. Provisional ApplicationNo. 61/381,764, filed on Sep. 10, 2010, all of which are incorporatedherein by reference.

This invention relates, inter alia, to the use of certain compounds inthe treatment of a condition ameliorated by the inhibition of the A₁receptor or the A_(2a) receptor.

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

Parkinson's Disease (PD) is a common progressive neurodegenerativedisorder with an estimated prevalence of 0.3 percent in the generalpopulation, rising to 5 percent in those over 85. The disease ischaracterised by tremor, rigidity and bradykinesia, which are caused bythe degeneration of dopaminergic neurons in the substantia nigra parscompacta and a resulting depletion of dopamine in the striatum.

Due to an ageing population, the incidence of Parkinson's disease isrising. However, the most effective pharmacological treatment for thedisease is still Levodopa (L-dopa), fifty years after its discovery asan antiparkinsonian agent (Chemical & Engineering News 2005, 83(25)).

L-dopa is the precursor of dopamine and achieves its pharmacologicaleffect by increasing dopaminergic transmission (i.e. by raising thelevel of dopamine in the striatum). The physiological effect of L-dopacan also be achieved by the administration of directly-acting dopamineagonists such as bromocriptine or pergolide. While the above treatmentsare initially very effective at controlling some of the symptoms ofParkinson's Disease, particularly rigidity, continuing use results in awide range of side effects that can be distressing to the patient (e.g.involuntary movements known as dyskinesias).

Other treatments include inhibition of the dopamine metabolizing enzymescatechol-o-methyl transferase (COMT) or monoamine oxidases (MAOIs), orthe use of anticholinergics. However, these treatments only provide mildto moderate benefit and suffer from a range of adverse side effects.

Adenosine is known to be an endogenous modulator of a number ofphysiological functions. For example, adenosine acts on thecardiovascular system and is a strong vasodilator and a cardiacdepressor and is known to have cardioprotective properties (see e.g.Norton et al. Am J Physiol. 1999; 276(2 Pt 2), H341-9; and Auchampachand Bolli Am J Physiol. 1999; 276(3 Pt 2), H1113-6). Effects ofadenosine on the central nervous system include sedative, anxiolytic andantiepileptic effects. Further, adenosine acts on the respiratory systemby inducing bronchoconstriction. In the kidneys, adenosine exerts abiphasic action, inducing vasoconstriction at low concentrations andvasodilation at high doses, meaning that adenosine may be involved inthe pathology of certain types of acute kidney failure(Costello-Boerrigter, et al. Med Clin North Am. 2003 March: 87(2),475-91; Gottlieb, Drugs. 2001, 61(10), 1387-93). Adenosine also acts asa lipolysis inhibitor on fat cells (Feoktistov, et al., Pharmacol. Rev.1997, 49, 381-402) and as an anti-aggregant on platelets.

The action of adenosine is mediated by a family of G-protein coupledreceptors. Biochemical and pharmacological studies, together withadvances in molecular biology, have allowed the identification of atleast four subtypes of adenosine receptors, which have been classifiedas adenosine A₁, A_(2a), A_(2b) and A₃. The A₁ and A₃ receptors inhibitthe activity of the enzyme adenylate cyclase, whereas the A_(2a) andA_(2b) receptors stimulate the activity of the same enzyme, therebymodulating the level of cyclic AMP in cells.

In the central nervous system, adenosine is a potent endogenousneuromodulator, which controls the presynaptic release of manyneurotransmitters and is thus involved in motor function, sleep,anxiety, pain and psychomotor activity. The main adenosine receptorsubtypes in the brain are A₁ and A_(2a). While the A₁ adenosine receptorsubtype is found throughout the brain in high density, the distributionof the A_(2a) receptor is more restricted and it is found in highdensity in the striatum (caudate-putamen, nucleus accumbens, olfactorytubercule), where it is co-localized with the dopamine D2 receptor onstriatopallidal output neurons. The discrete localization of the A_(2a)receptor within the striatum and its ability to functionally antagonizethe actions of the D2 receptor has led to the suggestion of thepotential utility of A_(2a) receptor antagonists for the symptomatictreatment of Parkinson's disease (see, for example, Cunha et al., CurrPharm Des. 2008, 14(15), 1512-1524).

Hence, A_(2a) antagonists can improve motor impairment due toneurodegenerative diseases such as Parkinson's, Huntington's andAlzheimer's disease (Tuite P, et al., J. Expert Opin. Investig. Drugs.2003; 12, 1335-52: Popoli P. et al. J Neurosci. 2002; 22, 1967-75; andDalrlgna, et al., Experimental Neurology, 2007, 241-245). Furthermore,A_(2a) antagonists may be employed for the treatment of: attentionrelated disorders such as attention deficit disorder (ADD) and attentiondeficit hyperactivity disorder (ADHD); psychoses; stroke, extrapyramidal syndrome (e.g., dystonia, akathisia, pseudoparkinsonism andtardive dyskinesia (see Jenner P. J Neurol. 2000; 247 Suppl2: 1143-50);and disorders of abnormal movement such as restless leg syndrome (RLS)and periodic limb movement in sleep (PLMS) (see, for example WO02/055083, WO 05/044245, WO 06/132275 and Happe S. et al.,Neuropsychobiology. 2003, 48, 82-6). Adenosine A_(2a) antagonists aredisclosed in US 2007037033 as useful agents for the treatment ofamyotrophic lateral sclerosis. WO 01/058241 discloses the treatment ofcirrhosis, fibrosis and fatty liver by employing adenosine A_(2a)antagonists. WO 06/009698 describes adenosine A_(2a) antagonists asuseful for the mitigation of addictive behaviour. It has been recentlydemonstrated that adenosine A_(2a) antagonists may be employed for thetreatment and prevention of dermal fibrosis in diseases such asscleroderma (Chan et al. Arthritis & Rheumatism, 2006, 54(8),2632-2642).

In addition, A_(2a) antagonists may have therapeutic potential asneuroprotectants (Stone T W. et al., Drag. Dev. Res. 2001, 52, 323-330),in the treatment of sleep disorders (Dunwiddie T V et al., Ann. Rev.Neurosci. 2001, 24, 31-55) and migraine (Kurokowa et al., 2009. ProgramNo. 714.4/8101, 2009 Neuroscience Meeting Planner. Chicago, Ill.:Society for Neuroscience).

Therapeutic uses for compounds that target A₁ receptors are diverse(see, for example Nature Reviews Drug Discovery 5, 2006, 247-264:Journal of Pharmacology and Experimental Therapeutics 323(2), 2007, 708to 719; British Journal of Pharmacology, 155, 2008, 475 to 486; Journalof the American College of Cardiology 50(16), 2007, 1551-1560;Pharmacology and Therapeutics 123, 2009, 105 to 116).

Adenosine A₁ receptors are expressed in the kidney and mediateadenosine's effects on both proximal tubular reabsorption and tubularglomerular feedback. Therefore blockade of the A₁ receptor will lead toinhibition of proximal tubular sodium reabsorption which could bebeneficial in diseases such as congestive heart failure, chronic renaldisease and cirrhosis (Gellai et al., 1998, J Pharmacol Exp Ther 286,1191-1196; J Am Coil Cardiol, 2007; 50:1551-1560). Compounds beingdeveloped as adenosine A₁ receptor antagonists for acute renal failureinclude rolofylline by Merck and derenofylline by Astellas. Adenosine A₁receptor antagonists may be employed to treat oedema (Satoh et al.,2000. Gastroenterol, 119(3):829-36), macular degeneration and cirrhosis.

While compounds with significant biological activity at multipleadenosine receptor subtypes may be therapeutically useful, they maycause unwanted side-effects. For example (as described in Gessi S et al.Pharmacol. Ther. 117(1), 2008, 123-140), adenosine A₃ receptorantagonism has various effects, such as an increased propensity fortissue damage following ischaemia (e.g. in the CNS, heart, kidney, lungand eye), increased reperfusion injury, increased neurodegeneration inresponse to hypoxia, potentially deleterious effects on motor functionor pain thresholds, immunosuppression or immunostimulation.

A number of compounds are currently being developed as A_(2a) receptorantagonists for the treatment of Parkinson's Disease. These compoundsinclude KW6002 (istradefylline,8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione)by Kyowa Hakko Kogyo, SCH-420814 (preladenant,2-(furan-2-yl)-7-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-1-yl]ethyl]-7H-pyrazolo[4,3-e][1,2,4]-triazolo[1,5-c]pyrimidin-5-amine)by Schering-Plough/Merck, BIIB014 by Biogen Idec, Lu AA47070 byLundbeck, ST-1535 by Sigma-Tau Farm Riunite SpA. SYN 115 by Synosia, andASP 5854 by Astellas.

However, the compounds mentioned above suffer from a number ofdrawbacks, such as low solubility (KW6002, SCH-420814, BIIB014 and LuAA47070), light sensitivity (KW6002), low selectivity (Lu AA47070 andASP 5854), potential toxicity due to the inclusion of known potentialtoxicophores (SCH-420814 and BIIB014) and limited efficacy in vivo(KW6002).

International patent applications WO 92/02513, WO 00/66568, WO03/077921, WO 2005/117883, WO 2006/051311, WO 2006/113704 and WO2009/090431, US patent application publications US 2004/0102436, US2004/0229873, US 2007/0135437, European patent publication No. 1 400 518and GB patent No. 1,604,085 disclose 1,2,4-triazine compounds withvarying biological activities. There is no suggestion or disclosure inthe documents above of 1,2,4-triazine compounds bearing the requiredsubstitution pattern required herein, or that any of the compoundsdisclosed in the documents above might be useful as A₁ or, particularly,A_(2a) receptor antagonists.

U.S. Pat. No. 4,008,232 and French patent No. 2,869,906 disclose anumber of 1,2,4-triazine compounds for use in the treatment ofinflammation and as sun-block agents, respectively. Doig et al., Journalof Chromatography 1991 554(1-2), 181-189 discloses a metabolite of theanticonvulsant agent Lamotrigine. A number of 1,2,4-triazine compoundswith anticonvulsant activity are disclosed in Mallikarjuna et al. JZhejian Univ Sci B 2007 8(7), 526-532. A number of 1,2,4-triazinecompounds with antiviral activity are disclosed in Davidson et al.Journal of Pharmaceutical Sciences 67(5), 1978, 737-739. A number of1,2,4-triazine compounds are disclosed in Eid at al., Indian Journal ofChemistry, Section B 1990 29B(5) 435-439, Zou et al., Chinese Journal ofChemistry 1998 16(1), 58-64, Lu et al., Youji Huaxue 1992 12(6),605-607, Lu et al., Organic Preparations and Procedures International1992 24(3), 358-362 and Konno et al. Heterocycles 19(10), 1982, 1865-8.There is no suggestion or disclosure that any of the above compoundsmight be useful as A₁ or, particularly, A_(2a) receptor antagonists.

We have now discovered, surprisingly, that certain 1,2,4-triazinecompounds bearing certain substituents are useful as A₁ and,particularly, A_(2a) receptor antagonists.

Thus, according to the first aspect of the invention, there is provideda compound of formula I for use in the treatment of a condition ordisorder ameliorated by the inhibition of the A₁ or, particularly, theA_(2a) receptor, wherein the compound of formula I has the structure

wherein:

R¹ represents H or C₁₋₆ alkyl, which latter group may be optionallysubstituted by one or more of halo. OR^(2a) or NR^(2b)R^(2c);

L¹ and L² independently represent CH═CH, a direct bond, O, NR^(2a),S(O)_(p), CH₂ or C(O);

R^(2a), R^(2b), R^(2c) and R^(3a) independently represent H or C₁₋₆alkyl, which latter group is optionally substituted by one or more haloatoms;

A represents Cy¹ or Het^(A);

Cy¹ represents a 5- to 14-membered aromatic, fully saturated orpartially unsaturated carbocyclic ring system comprising one, two orthree rings, which Cy¹ group is optionally substituted by one or moreR^(4a) substituents:

Het^(A) represents a 5- to 14-membered heterocyclic group that may bearomatic, fully saturated or partially unsaturated, and which containsone or more heteroatoms selected from O, S and N, which heterocyclicgroup may comprise one, two or three rings and which Het^(A) group isoptionally substituted by one or more R^(4b) substituents;

B represents a Cy² or Het^(B);

Cy² represents a 3- to 10-membered aromatic, fully saturated orpartially unsaturated carbocyclic ring system comprising one or tworings, which Cy² group is optionally substituted by one or more R^(4c)substituents;

Het^(B) represents a 3- to 10-membered heterocyclic group that may bearomatic, fully saturated or partially unsaturated, and which containsone or more heteroatoms selected from O, S and N, which heterocyclicgroup may comprise one or two rings and which Het^(B) group isoptionally substituted by one or more R^(4d) substituents;

R^(4a) to R^(4d) represent, independently at each occurrence,

-   (a) halo,-   (b) CN,-   (c) C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, which latter three    groups are optionally substituted by one or more substituents    selected from halo, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₈    alkynyl (which latter three groups are optionally substituted by one    or more substituents selected from OH, ═O, halo, C₁₋₄ alkyl and C₁₋₄    alkoxy), OR^(5a), S(O)_(q)R^(5b), S(O)₂N(R^(5c))(R^(5d)),    N(R^(5e))S(O)₂R^(5f), N(R^(5g))(R^(5h)), B¹—C(G¹)-B²—R^(5i), aryl    and Het¹,-   (d) Cy³, which Cy⁵ group is optionally substituted by one or more    substituents selected from halo, nitro, CN, C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl (which latter three groups are optionally    substituted by one or more substituents selected from OH, ═O, halo,    C₁₋₄ alkyl and C₁₋₄ alkoxy), OR^(6a), S(O)R^(6b),    S(O)₂N(R^(6c))(R^(6d)), N(R^(6e))S(O)₂R^(6f), N(R^(6g))(R^(6h)),    B³—C(G¹)-B⁴—R^(6i), aryl and Het²,-   (e) Het^(a), which Het^(a) group is optionally substituted by one or    more substituents selected from halo, nitro, CN, C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₄ alkynyl (which latter three groups are optionally    substituted by one or more substituents selected from OH, ═O, halo,    C₁₋₄ alkyl and C₁₋₄ alkoxy), OR^(7a), S(O)_(q)R^(7b),    S(O)₂N(R^(7c))(R^(7d)), N(R^(7e))S(O)₂R^(7f), N(R^(7g))(R^(7h)),    B⁵—C(G¹)-B⁶—R^(7i), aryl and Het³,-   (f) OR⁸,-   (g) S(O)_(r)R^(9a),-   (h) S(O)₂N(R^(9b))(R^(9c)),-   (i) N(R^(9d))S(O)₂R^(9e),-   (j) N(R^(9f))(R^(9g)),-   (k) B⁷—C(G¹)-B—R^(9h).-   (l) ═O,-   (m) ═S,    or when two R^(4a), R^(4b), R^(4c) or R^(4d) groups are attached to    the same carbon atom in a non-aromatic portion of a Cy¹, Het^(A),    Cy² or Het^(B) group, they may form, together with the carbon atom    to which they are attached, a saturated or unsaturated 3 to    6-membered ring, which ring optionally contains one to three    heteroatoms selected from O, S and N, and which ring is optionally    substituted by one or more R^(9i) substituents;

G¹ represents, independently at each occurrence, O, S or NR^(5i);

R⁸ represents, independently at each occurrence,

-   -   H,    -   Cy³, Het^(a), aryl^(a), C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,        C₃₋₅ cycloalkyl, which latter seven groups are optionally        substituted by one or more substituents selected from halo, —CN,        C₃₋₆ cycloalkyl, aryl, Het⁴, —C(O)OR¹⁰, —C(O)R¹¹,        —C(O)N(R^(N1))(R^(N2)), S(O)_(r)R^(9aa),        S(O)₂N(R^(9ba))(R^(9ca)), N(R^(da))S(O)₂R^(9ea) and        N(R^(9fa))(R^(9ga));

Cy³ represents, independently at each occurrence, a 3- to 6-memberedaromatic, fully saturated or partially unsaturated carbocyclic ring;

Het^(a) represents, independently at each occurrence, a 3- to 6-memberedheterocyclic ring that may be aromatic, fully saturated or partiallyunsaturated and which contains one or more heteroatoms selected from O,S and N;

R¹⁰ and R¹¹ independently represent

-   (a) H,-   (b) C₁₋₆ alkyl optionally substituted by one or more substituents    selected from halo, aryl, —N(R^(N3))(R^(N4)) and —OR^(a),-   (c) aryl or-   (d) C₃₋₇ cycloalkyl (which group is optionally substituted by one or    more substituents selected from OH, ═O, halo, C₁₋₄ alkyl and C₁₋₄    alkoxy);

B¹ to B⁸ independently represent, at each occurrence, a direct bond, O,S or N(R^(N3));

each aryl^(a) independently represents a C₆₋₁₄ carbocyclic aromaticgroup, which group may comprise one, two or three rings;

-   -   each aryl independently represents a C₆₋₁₄ carbocyclic aromatic        group, which group may comprise one, two or three rings and may        be substituted by one or more substituents selected from    -   halo,    -   C₁₋₆ alkyl, which latter group is optionally substituted by one        or more substituents selected from halo, —N(R^(N4))(R^(N5)) and        —OR^(a), and —OR^(a);

Het¹ to Het⁴ independently represent 4- to 14-membered heterocyclicgroups containing one or more heteroatoms selected from O, S and N,which heterocyclic groups may comprise one, two or three rings and maybe substituted by one or more substituents selected from

-   -   halo,    -   C₁₋₆ alkyl, which latter group is optionally substituted by one        or more substituents selected from halo, —N(R^(N6))(R^(N7)) and        —OR^(a), and —OR^(a);

R^(N1) to R^(N7) independently represent

-   -   H,    -   C₁₋₆ alkyl or C₃₋₆ cycloalkyl, which latter two groups are        optionally substituted by one or more substituents selected from        halo and —OR^(a);

R^(a) represents, independently at each occurrence,

-   (a) H;-   (b) C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl,    C₄₋₁₂ cycloalkenyl, which latter five groups are optionally    substituted by one or more substituents selected from halo, nitro,    CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl (which    latter four groups are optionally substituted by one or more    substituents selected from OH, ═O, halo, C₁₋₄ alkyl and C₁₋₄    alkoxy), OR^(12a), S(O)_(q)R^(12b), S(O)₂N(R^(12c))(R^(12d)),    N(R^(12e))S(O)₂R^(12f), N(R^(12g))(R^(12h)), B⁹—C(G²)-B¹⁰—R^(12i),    aryl¹ and Het^(b), and which C₃₋₁₂ cycloalkyl or C₄₋₁₂ cycloalkenyl    groups may additionally be substituted by ═O.-   (c) S(O)_(r)R^(13a),-   (d) S(O)₂N(R^(13b))(R^(13c)) or-   (e) C(O)—B¹¹—R^(13d);

R^(5a) to R^(5j), R^(6a) to R^(6i), R^(7a) to R^(7i), R^(9a) to R^(9i),R^(9aa) to R^(9ga), R^(12a) to R^(12i) and R^(13a) to R^(13d)independently represent, at each occurrence,

-   (a) H,-   (b) C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl which latter three    groups are optionally substituted by one or more substituents    selected from halo, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₃₋₆ cycloalkyl (which latter three groups are optionally    substituted by one or more substituents selected from OH, ═O, halo,    C₁₋₄ alkyl and C₁₋₄ alkoxy), OR^(5aa), S(O)_(q)R^(5ab),    S(O)₂N(R^(5ac))(R^(5ad)), N(R^(5ae))S(O)₂R^(5af),    N(R^(5ag))(R^(5ah)), B¹²—C(G²)-B¹³—R^(5ai), aryl¹ and Het^(c);-   (c) C₃₋₁₀ cycloalkyl, or C₄₋₁₀ cycloalkenyl (which latter two groups    are optionally substituted by one or more substituents selected from    halo, OH, ═O, C₁₋₆ alkyl and C₁₋₆ alkoxy),-   (d) Het^(d);

G² represents, independently at each occurrence, O, S, or NR^(5aj);

R^(5aa) to R^(5aj) independently represent at each occurrence,

-   (a) H,-   (b) C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl which latter three groups    are optionally substituted by one or more substituents selected from    halo, nitro, CN, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl (which    latter three groups are optionally substituted by one or more    substituents selected from OH, ═O, halo, C₁₋₄ alkyl and C₁₋₄    alkoxy),-   (c) C₃₋₆ cycloalkyl, or C₄₋₆ cycloalkenyl (which latter two groups    are optionally substituted by one or more substituents selected from    halo, OH, ═O, C₁₋₄ alkyl and C₁₋₄ alkoxy),-   (d) Het^(e),    or R^(5ag) and R^(5ah) may represent, together with the nitrogen    atom to which they are attached, a 3- to 10-membered heterocyclic    ring that may be aromatic, fully saturated or partially unsaturated    and which may additionally contain one or more heteroatoms selected    from O, S and N, which heterocyclic ring is optionally substituted    by one or more substituents selected from halo, nitro, CN, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl (which latter three groups are    optionally substituted by one or more substituents selected from OH,    ═O, halo, C₁₋₄ alkyl and C₁₋₄ alkoxy);

B⁹ to B¹³ independently represent a direct bond, O, S or N(R^(N8));

aryl¹ represents, independently at each occurrence, a C₆₋₁₀ carbocyclicaromatic group, which group may comprise one or two rings and may besubstituted by one or more substituents selected from

-   -   halo,    -   C₁₋₆ alkyl, which latter group is optionally substituted by one        or more substituents selected from halo, —N(R^(N10))(R^(N11))        and C₁₋₆ alkoxy (which latter substituent is optionally        substituted by one or more halo atoms), and    -   C₁₋₆ alkoxy (which latter substituent is optionally substituted        by one or more halo atoms);

R^(N8), R^(N10) and R^(N11) independently represent

-   -   H,    -   C₁₋₆ alkyl or C₃₋₆ cycloalkyl, which latter two groups are        optionally substituted by one or more halo atoms;

Het^(b) represents a 5- or 6-membered that may be aromatic, fullysaturated or partially unsaturated and which contains one or moreheteroatoms selected from O, S and N, which heterocyclic group may besubstituted by one or more substituents selected from halo, ═O and C₁₋₆alkyl;

Het^(c) to Het^(e) independently represent, a 3- to 6-memberedheterocyclic ring that may be aromatic, fully saturated or partiallyunsaturated and which contains one or more heteroatoms selected from O,S and N, which Het^(c) to Het^(e) groups are optionally substituted byone or more substituents selected from halo, nitro, CN, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl (which latter three groups are optionallysubstituted by one or more substituents selected from OH, ═O, halo, C₁₋₄alkyl and C₁₋₄ alkoxy);

p, q and r independently represent at each occurrence 0, 1 or 2; and

unless otherwise specified alkyl, alkenyl, alkynyl, cycloalkyl and thealkyl part of alkoxy groups may be substituted by one or more haloatoms.

References herein (in any aspect or embodiment of the invention) tocompounds of formula I includes references to such compounds per se, totautomers of such compounds, as well as to pharmaceutically acceptablesalts or solvates, or pharmaceutically functional derivatives of suchcompounds.

Pharmaceutically acceptable salts that may be mentioned include acidaddition salts and base addition salts. Such salts may be formed byconventional means, for example by reaction of a free acid or a freebase form of a compound of formula I with one or more equivalents of anappropriate acid or base, optionally in a solvent, or in a medium inwhich the salt is insoluble, followed by removal of said solvent, orsaid medium, using standard techniques (e.g. in vacuo, by freeze-dryingor by filtration). Salts may also be prepared by exchanging acounter-ion of a compound of formula I in the form of a salt withanother counter-ion, for example using a suitable ion exchange resin.

Examples of pharmaceutically acceptable salts include acid additionsalts derived from mineral acids and organic acids, and salts derivedfrom metals such as sodium, magnesium, or preferably, potassium andcalcium.

Examples of acid addition salts include acid addition salts formed withacetic, 2,2-dichloroacetic, adipic, alginic, aryl sulfonic acids (e.g.benzenesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic andp-toluenesulfonic), ascorbic (e.g. L-ascorbic), L-aspartic, benzoic,4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic.(+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic,citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic, ethanesufonic,2-hydroxyethanesufonic, formic, fumaric, galactaric, gentisic,glucoheptonic, gluconic (e.g. D-gluconic), glucuronic (e.g.D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric, glycolic,hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g.(+)-L-lactic and (±)-DL-lactic), lactobionic, maleic, malic (e.g.(−)-L-malic), malonic, (±)-DL-mandelic, metaphosphoric, methanesulfonic,1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic,palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic,4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic,tartaric (e.g. (+)-L-tartaric), thiocyanic, undecylenic and valericacids.

Particular examples of salts are salts derived from mineral acids suchas hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric andsulfuric acids; from organic acids, such as tartaric, acetic, citric,malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic,arylsulfonic acids; and from metals such as sodium, magnesium, orpreferably, potassium and calcium.

As mentioned above, also encompassed by formula I are any solvates ofthe compounds and their salts. Preferred solvates are solvates formed bythe incorporation into the solid state structure (e.g. crystalstructure) of the compounds of the invention of molecules of a non-toxicpharmaceutically acceptable solvent (referred to below as the solvatingsolvent). Examples of such solvents include water, alcohols (such asethanol, isopropanol and butanol) and dimethylsulfoxide. Solvates can beprepared by recrystallising the compounds of the invention with asolvent or mixture of solvents containing the solvating solvent. Whetheror not a solvate has been formed in any given instance can be determinedby subjecting crystals of the compound to analysis using well known andstandard techniques such as thermogravimetric analysis (TGE),differential scanning calorimetry (DSC) and X-ray crystallography.

The solvates can be stoichiometric or non-stoichiometric solvates.Particularly preferred solvates are hydrates, and examples of hydratesinclude hemihydrates, monohydrates and dihydrates.

For a more detailed discussion of solvates and the methods used to makeand characterise them, see Bryn et al., Solid-State Chemistry of Drugs,Second Edition, published by SSCI, Inc of West Lafayette, Ind., USA,1999. ISBN 0-967-06710-3.

“Pharmaceutically functional derivatives” of compounds of formula I asdefined herein includes ester derivatives and/or derivatives that have,or provide for, the same biological function and/or activity as anyrelevant compound of the invention. Thus, for the purposes of thisinvention, the term also includes prodrugs of compounds of formula I.

The term “prodrug” of a relevant compound of formula I includes anycompound that, following oral or parenteral administration, ismetabolised in vivo to form that compound in anexperimentally-detectable amount, and within a predetermined time (e.g.within a dosing interval of between 6 and 24 hours (i.e. once to fourtimes daily)).

Prodrugs of compounds of formula I may be prepared by modifyingfunctional groups present on the compound in such a way that themodifications are cleaved, in vivo when such prodrug is administered toa mammalian subject. The modifications typically are achieved bysynthesizing the parent compound with a prodrug substituent. Prodrugsinclude compounds of formula I wherein a hydroxyl, amino, sulfhydryl,carboxyl or carbonyl group in a compound of formula I is bonded to anygroup that may be cleaved in vivo to regenerate the free hydroxyl,amino, sulfhydryl, carboxyl or carbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters andcarbamates of hydroxyl functional groups, esters groups of carboxylfunctional groups, N-acyl derivatives and N-Mannich bases. Generalinformation on prodrugs may be found e.g. in Bundegaard, H. “Design ofProdrugs” p. 1-92, Elsevier, New York-Oxford (1985).

Compounds of formula I, as well as pharmaceutically acceptable salts,solvates and pharmaceutically functional derivatives of such compoundsare, for the sake of brevity, hereinafter referred to together as the“compounds of formula I”.

Compounds of formula I may contain double bonds and may thus exist as E(entgegen) and Z (zusammen) geometric isomers about each individualdouble bond. All such isomers and mixtures thereof are included withinthe scope of the invention.

Compounds of formula I may exist as regioisomers and may also exhibittautomerism. All tautomeric forms and mixtures thereof are includedwithin the scope of the invention. For example, the following tautomersare included within the scope of the invention:

Compounds of formula I may contain one or more asymmetric carbon atomsand may therefore exhibit optical and/or diastereoisomerism.Diastereoisomers may be separated using conventional techniques, e.g.chromatography or fractional crystallisation. The various stereoisomersmay be isolated by separation of a racemic or other mixture of thecompounds using conventional, e.g. fractional crystallisation or HPLC,techniques. Alternatively the desired optical isomers may be made byreaction of the appropriate optically active starting materials underconditions which will not cause racemisation or epimerisation (i.e. a‘chiral pool’ method), by reaction of the appropriate starting materialwith a ‘chiral auxiliary’ which can subsequently be removed at asuitable stage, by derivatisation (i.e. a resolution, including adynamic resolution), for example with a homochiral acid followed byseparation of the diastereomeric derivatives by conventional means suchas chromatography, or by reaction with an appropriate chiral reagent orchiral catalyst all under conditions known to the skilled person. Allstereoisomers and mixtures thereof are included within the scope of theinvention.

For the avoidance of doubt, compounds of formula I may contain thestated atoms in any of their isotopic forms. In this respect,embodiments of the invention that may be mentioned include those inwhich:

-   (a) the compound of formula I is not isotopically enriched or    labelled with respect to any atoms of the compound; and-   (b) the compound of formula I is isotopically enriched or labelled    with respect to one or more atoms of the compound.

The compound for use mentioned in the above-mentioned aspect of theinvention may be utilised in a method of medical treatment. Thus,according to further aspects of the invention, there is provided:

-   (i) the use of a compound formula I for the manufacture of a    medicament for the treatment of a condition or disorder ameliorated    by inhibition of the A₁ or, particularly, the A_(2a) receptor; and-   (ii) a method of treatment of a disorder or condition ameliorated by    antagonising the A₁ or, particularly, the A_(2a) receptor, which    method comprises the administration of an effective amount of a    compound of formula I to a patient in need of such treatment.

The term “disorder or condition ameliorated by the inhibition of the A₁or, particularly, the A_(2a) receptor” will be understood by thoseskilled in the art to include: heart failure (such as acutedecompensated heart failure and congestive heart failure); kidneyfailure (e.g. caused by heart failure); oedema; cancer (such asprostate, rectal, renal, ovarian, endometrial, thyroid, pancreatic,particularly breast, colon, bladder, brain, glia, melanoma, pineal glandand, more particularly, lung cancer (e.g. Lewis lung carcinoma));diabetes; diarrhea; macular degeneration (such as macular degenerationcaused by angiogenesis (e.g. retinal angiogenesis)); or, particularly(e.g. for disorders or conditions ameliorated by the inhibition of theA_(2a) receptor), a disease of the central nervous system such asdepression, a cognitive function disease, a neurodegenerative disease(such as Parkinson's disease, Huntington's disease, Alzheimer's disease,amyotrophic lateral sclerosis) and psychoses; an attention relateddisorder (such as attention deficit disorder (ADD) and attention deficithyperactivity disorder (ADHD)); extra pyramidal syndrome (e.g. dystonia,akathisia, pseudoparkinsonism and tardive dyskinesia); a disorder ofabnormal movement (such as restless leg syndrome (RLS) and periodic limbmovement in sleep (PLMS)); cirrhosis; liver fibrosis; fatty liver;dermal fibrosis (e.g. in diseases such as scleroderma); a sleepdisorder; stroke; brain injury and neuroinflammation (e.g. migraine orany disorder or condition caused by ischemia, stroke, head injury or CNSinflammation); addictive behaviour.

Thus, further aspects of the invention relate to the following.

-   (a) A compound of formula I, as hereinbefore defined, for use in the    treatment of a condition or disorder selected from heart failure    (such as acute decompensated heart failure and congestive heart    failure); kidney failure (e.g. caused by heart failure); oedema;    cancer (such as prostate, rectal, renal, ovarian, endometrial,    thyroid, pancreatic, particularly breast, colon, bladder, brain,    glia, melanoma, pineal gland and, more particularly, lung cancer    (e.g. Lewis lung carcinoma)); diabetes; diarrhea; macular    degeneration (such as macular degeneration caused by angiogenesis    (e.g. retinal angiogenesis)); or, particularly (e.g. for disorders    or conditions ameliorated by the inhibition of the A_(2a) receptor),    a disease of the central nervous system such as depression, a    cognitive function disease, a neurodegenerative disease (such as    Parkinson's disease, Huntington's disease, Alzheimer's disease,    amyotrophic lateral sclerosis) and psychoses; an attention related    disorder (such as attention deficit disorder (ADD) and attention    deficit hyperactivity disorder (ADHD)); extra pyramidal syndrome    (e.g. dystonia, akathisia, pseudoparkinsonism and tardive    dyskinesia): a disorder of abnormal movement (such as restless leg    syndrome (RLS) and periodic limb movement in sleep (PLMS));    cirrhosis; liver fibrosis; fatty liver; dermal fibrosis (e.g. in    diseases such as scleroderma); a sleep disorder; stroke; brain    injury and neuroinflammation (e.g. migraine or any disorder or    condition caused by ischemia, stroke, head injury or CNS    inflammation): addictive behaviour.-   (b) Use of a compound of formula I, as hereinbefore defined, for the    preparation of a medicament for the treatment of a condition or    disorder selected from heart failure (such as acute decompensated    heart failure and congestive heart failure); kidney failure (e.g.    caused by heart failure); oedema; cancer (such as prostate, rectal,    renal, ovarian, endometrial, thyroid, pancreatic, particularly    breast, colon, bladder, brain, glia, melanoma, pineal gland and,    more particularly, lung cancer (e.g. Lewis lung carcinoma));    diabetes; diarrhea; macular degeneration (such as macular    degeneration caused by angiogenesis (e.g. retinal angiogenesis));    or, particularly (e.g. for disorders or conditions ameliorated by    the inhibition of the A_(2a) receptor), a disease of the central    nervous system such as depression, a cognitive function disease, a    neurodegenerative disease (such as Parkinson's disease, Huntington's    disease, Alzheimer's disease, amyotrophic lateral sclerosis) and    psychoses; an attention related disorder (such as attention deficit    disorder (ADD) and attention deficit hyperactivity disorder (ADHD));    extra pyramidal syndrome (e.g. dystonia, akathisia,    pseudoparkinsonism and tardive dyskinesia); a disorder of abnormal    movement (such as restless leg syndrome (RLS) and periodic limb    movement in sleep (PLMS)); cirrhosis; liver fibrosis; fatty liver;    dermal fibrosis (e.g. in diseases such as scleroderma); a sleep    disorder; stroke; brain injury and neuroinflammation (e.g. migraine    or any disorder or condition caused by ischemia, stroke, head injury    or CNS inflammation); addictive behaviour.-   (c) A method of treatment of a disorder or condition selected from    heart failure (such as acute decompensated heart failure and    congestive heart failure); kidney failure (e.g. caused by heart    failure); oedema; cancer (such as prostate, rectal, renal, ovarian,    endometrial, thyroid, pancreatic, particularly breast, colon,    bladder, brain, glia, melanoma, pineal gland and, more particularly,    lung cancer (e.g. Lewis lung carcinoma)); diabetes; diarrhea;    macular degeneration (such as macular degeneration caused by    angiogenesis (e.g. retinal angiogenesis)); or, particularly (e.g.    for disorders or conditions ameliorated by the inhibition of the    A_(2a) receptor), a disease of the central nervous system such as    depression, a cognitive function disease, a neurodegenerative    disease (such as Parkinson's disease, Huntington's disease,    Alzheimer's disease, amyotrophic lateral sclerosis) and psychoses;    an attention related disorder (such as attention deficit disorder    (ADD) and attention deficit hyperactivity disorder (ADHD)); extra    pyramidal syndrome (e.g. dystonia, akathisia, pseudoparkinsonism and    tardive dyskinesia); a disorder of abnormal movement (such as    restless leg syndrome (RLS) and periodic limb movement in sleep    (PLMS)); cirrhosis; liver fibrosis; fatty liver; dermal fibrosis    (e.g. in diseases such as scleroderma); a sleep disorder: stroke;    brain injury and neuroinflammation (e.g. migraine or any disorder or    condition caused by ischemia, stroke, head injury or CNS    inflammation); addictive behaviour, which method comprises the    administration of an effective amount of a compound of formula I, as    hereinbefore defined.

Particular disorders or conditions that may be mentioned in relation tothe aspects of the invention described hereinbefore include addictivebehaviour, ADHD and, particularly, neurodegenerative disease (e.g.Alzheimer's, Huntington's, and, particularly, Parkinson's Disease).

Embodiments of the invention that may be mentioned include those inwhich the compounds of formula I selectively inhibit the A₁ and A_(2a)receptor subtypes.

When used herein in relation to inhibition of the A₁ or A_(2a) receptor,the terms “selective” and “selectivity” includes references to thebinding of a compound to the A₁ or, more particularly, A_(2a) receptorwith an IC₅₀ value that is at least 10-fold lower (e.g. at least 20-,50-, 100-, 500- or 1000-fold lower) than the IC₅₀ value determined forthe binding of the same compound to the A₃, receptor sub-type at thesame temperature (e.g. room temperature, such as 298 K).

Embodiments of the invention that may also be mentioned include those inwhich the compounds of formula I are selective inhibitors of the A_(2a)receptor.

When used herein in relation to inhibition of the A_(2a) receptor, theterms “selective” and “selectivity” includes references to the bindingof a compound to the A_(2a) receptor with an IC₅₀ value that is at least10-fold lower (e.g. at least 20-, 50-, 100-, 500- or 1000-fold lower)than the IC₅₀ value determined for the binding of the same compound toanother adenosine receptor subtype (e.g. the A_(2b), particularly A₁,or, more particularly, A₃, receptor sub-type) at the same temperature(e.g. room temperature, such as 298 K). Selectivity for the A_(2a)receptor can be over one other adenosine receptor subtype but, incertain embodiments of the invention, is over two or more (e.g. allother) adenosine receptor subtypes.

Antagonising the A_(2a) receptor may have neuroprotective effects. Thus,according to further aspects of the invention there are provided:

-   (i) a compound of formula I for use as a neuroprotectant;-   (ii) the use of a compound of formula I for the manufacture of a    medicament for use as a neuroprotectant; and-   (iii) a method of mitigating damage to brain neurons caused by a    neurodegenerative disease (such as Parkinson's disease, Huntington's    disease, Alzheimer's disease or amyotrophic lateral sclerosis),    stroke or other cerebral trauma, neurotoxins (e.g. mercury and    compounds thereof, lead and compounds thereof, organic phosphates    and nitrogen mustards), CNS infections (e.g. meningitis,    encephalitis, poliomyelitis, tuberculosis, toxoplasmosis,    neurosyphilis) or drug use (e.g. cocaine), which method comprises    the administration of an effective amount of a compound of formula I    to a patient at risk of damage to brain neurons from    neurodegenerative disease, stroke or other cerebral trauma,    neurotoxins, CNS infections or drug use.

References herein to patients at risk of damage to brain neurons fromneurodegenerative disease, stroke or other cerebral trauma includereferences to patients who have been determined by clinical assessmentto have a higher than average risk (as determined, for example, bycomparison to normal individuals of the same age) of developing aneurodegenerative disease (e.g. Parkinson's disease, Huntington'sdisease. Alzheimer's disease or amyotrophic lateral sclerosis) or ofhaving a stroke.

Antagonising the A₁ receptor may have effects on kidney function. Thus,according to further aspects of the invention there are provided:

-   (i) a compound of formula I for use in mitigating kidney damage    caused by acute renal failure, oedema, heart failure, chronic renal    disease and/or cirrhosis;-   (ii) the use of a compound of formula I for the manufacture of a    medicament for mitigating kidney damage caused by acute renal    failure, oedema, heart failure, chronic renal disease and/or    cirrhosis; and-   (iii) a method of mitigating kidney damage caused by acute renal    failure, oedema, heart failure, chronic renal disease and/or    cirrhosis, which method comprises the administration of an effective    amount of a compound of formula I to a patient at risk of damage to    kidney function by acute renal failure, congestive heart failure,    chronic renal disease or cirrhosis.

References herein to kidney damage include, in particular, kidney damagecaused by acute renal failure.

References herein to patients at risk of damage to kidney function byacute renal failure, heart failure, chronic renal disease or cirrhosisinclude references to patients who have been determined by clinicalassessment to have a higher than average risk (as determined, forexample, by comparison to normal individuals of the same age) ofdeveloping acute renal failure, heart failure, chronic renal disease orcirrhosis.

For the avoidance of doubt, in the context of the present invention, theterm “treatment” includes references to therapeutic or palliativetreatment of patients in need of such treatment, as well as to theprophylactic treatment and/or diagnosis of patients which aresusceptible to the relevant disease states.

The terms “patient” and “patients” include references to mammalian (e.g.human) patients.

The term “effective amount” refers to an amount of a compound, whichconfers a therapeutic effect on the treated patient (e.g. sufficient totreat or prevent the disease). The effect may be objective (i.e.measurable by some test or marker) or subjective (i.e. the subject givesan indication of or feels an effect).

The term “halo”, when used herein, includes references to fluoro,chloro, bromo and iodo.

Unless otherwise stated, the term “carbocyclic” when used herein inconnection with groups Cy¹ and Cy² includes references to carbocyclicgroups (e.g. C₅₋₆ carbocyclic groups) that are mono-, bi- or tricyclicand which may be may be fully saturated, partly unsaturated or whollyaromatic in character. For example, Cy¹ and Cy² groups may be selectedfrom the group comprising of cyclobutyl, cyclobutenyl, cyclopropyl,cydopropenyl, particularly cyclopentyl, cyclopentenyl,(1Z,2Z,4Z,6Z,8Z)-cyclodecapentaenyl, more particularly, cyclohexyl,cyclohexenyl, indanyl, indenyl, napthalenyl (e.g.1,2,3,4-tetrahydronaphthyl), and, yet more particularly, phenyl). Thepoint of attachment of carbocyclic groups may be via any atom of thering system.

Unless otherwise stated herein, the term “heterocyclic”, when usedherein in connection with groups Het^(A) and Het^(B) includes referencesto heterocyclic groups which may be fully saturated, partly unsaturatedor wholly aromatic in character.

Thus Het^(A) and Het^(B) represent a 5- to 14- or a 3- to 10-memberedheterocyclic group, respectively, that may be aromatic, fully saturatedor partially unsaturated, and which contains one or more heteroatomsselected from O, S and N, which heterocyclic groups may comprise one,two or three rings and which Het^(A) or Het^(B) group is optionallysubstituted by one or more R^(4b) or R^(4d) substituents, respectively.

The heterocyclic group (e.g. Het^(A) or Het^(B)) may contain up to 5heteroatom ring members selected from O, N and S, and more particularlyup to 4 heteroatom ring members. For example, the heterocyclic group maycontain 1, 2 or 3 heteroatom ring members.

In one embodiment, Het^(A) and Het^(B) may each represent a monocyclic,bicyclic or tricyclic 5- to 14- or 3- to 10-membered heterocyclic group,respectively, containing 1, 2, 3 or 4 heteroatom ring members selectedfrom O, N and S. Within this subset, Het^(A) or Het^(B) (whereappropriate) may be selected, for example, from (i) monocyclicheterocyclic groups of 5 to 7 ring members containing 1, 2, 3 or 4heteroatom ring members selected from O, N and S; (ii) 6.5 fusedbicyclic heterocyclic groups of 9 ring members containing 1, 2, 3 or 4heteroatom ring members selected from O, N and S; (iii) 6.6 fusedbicyclic heterocyclic groups of 9 ring members containing 1, 2, 3 or 4heteroatom ring members selected from O, N and S; (iv) 6.5.6 fusedtricyclic heterocyclic groups of 13 ring members containing 1, 2, 3 or 4heteroatom ring members selected from O, N and S; (v) 6.6.6 fusedtricyclic heterocyclic groups of 14 ring members containing 1, 2, 3 or 4heteroatom ring members selected from O, N and S; and (vi) bridgedbicyclic heterocyclic groups of 7 or 8 ring members containing 1 or 2heteroatom ring members selected from O, N and S.

By “bridged ring systems” is meant ring systems in which two rings sharemore than two atoms, see for example Advanced Organic Chemistry, byJerry March, 4^(th) Edition, Wiley Interscience, pages 131-133, 1992.

In another embodiment, Het^(A) and Het^(B) may be the same or differentand each represents a monocyclic or bicyclic 5 to 10 memberedheterocyclic group containing 1, 2, 3 or 4 heteroatom ring membersselected from O, N and S. Within this subset, Het^(A) or Het^(B) may beselected, for example, from (i) monocyclic heterocyclic groups of 5 to 7ring members containing 1, 2, 3 or 4 heteroatom ring members selectedfrom O, N and S; (ii) 6.5 fused bicyclic heterocyclic groups of 9 ringmembers containing 1, 2, 3 or 4 heteroatom ring members selected from O,N and S; (iii) 6.6 fused bicyclic heterocyclic groups of 9 ring memberscontaining 1, 2, 3 or 4 heteroatom ring members selected from O, N andS; and (vi) bridged bicyclic heterocyclic groups of 7 or 8 ring memberscontaining 1 or 2 heteroatom ring members selected from O, N and S.

In each of the foregoing subsets of compounds, when Het^(A) is apyridonyl group, it may be other than a pyridin-2-one group (for exampleit may be a pyridin-4-one group).

For example, Het^(A) and Het^(B) may be selected from the groupcomprising of azepinyl, diazepinyl, dihydrofuranyl (e.g.2,3-dihydrofuranyl, 2,5-dyhdrofuranyl), 4,5-dihydro-1H-maleimido,dioxolanyl, furanyl, furazanyl, hydantoinyl, imidazolyl, isothiaziolyl,isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2- or1,3-oxazinanyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl,pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinonyl,pyrrolinyl, pyrrolyl, sulfolanyl, 3-suffolenyl, tetrahydrofuranyl,tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thiomorpholinyl,thiophenetyl, triazolyl, more particularly, dihydropyranyl (e.g.3,4-dihydropyranyl, 3,6-dihydropyranyl), dioxanyl, hexahydropyrimidinyl,isobenzofuranyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl,tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl,1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl,tetrahydrothiophenyl, tetramethylenesufoxide, thiazolidinyl, triazinanyland the like. The point of attachment of carbocyclic groups may be viaany atom of the ring system.

Definitions of A that may be mentioned therefore include indolinonyl,pyridazinonyl, octahydroisoquinolin-(1H)-yl,2,2,6,6,-tetramethyl-3,6-dihydro-2H-pyran-4-yl, indolinonyl,6-oxa-9-azaspiro[4.5]decanyl, octahydroisoquinolin-(1H)-yl,hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, pyridazinonyl or, particularly,cyclopentyl, cyclopentenyl, dihydrofuranyl (e.g 2,3-dihydrofuranyl,2,5-dyhdrofuranyl), 4,5-dihydro-1H-maleimido, dioxolanyl, furanyl,furazanyl, hydantoinyl, imidazolyl, isoxazolyl, isoxazolidinyl,isothiaziolyl, oxadiazolyl, oxazolyl, pyrrolidinyl, pyrrolidinonyl,pyrazolyl, pyrrolinyl (e.g. 3-pyrrolinyl), pyrrolyl, sulfolanyl,3-sulfolenyl, tetrahydrofuranyl, tetramethylenesulfoxide, tetrazolyl,thiadiazolyl, thiazolyl, thiazolidinyl, thienyl, triazolyl, or moreparticularly, acridinyl, 2-azabicyclo[4.1.0]heptanyl,1-azabicyclo-[2.2.2]octanyl, azepinyl, benzimidazolyl, benzisothiazolyl,benzisoxazolyl, benzodioxanyl, benzodioxepanyl, benzodioxepinyl,benzodioxolyl, benzofuranyl, benzofurazanyl, benzo[c]isoxazolidinyl,benzomorpholinyl, 2,1,3-benzoxadiazolyl, benzoxazinyl (including3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolidinyl, benzoxazolyl,benzopyrazolyl, benzo[e]pyrimidine, 2,1,3-benzothiadiazolyl,benzothiazolyl, benzothienyl, benzotriazolyl, carbazolyl, chromanyl,chromenyl, cinnolinyl, (1Z,2Z,4Z,6Z,8Z)-cyclodecapentaenyl, cyclohexyl,cyclohexenyl, decahydroisoquinolenyl, diazepinyl,2,3-dihydrobenzimidazolyl, 2,3-dihydrobenzo[b]furanyl,1,3-dihydrobenzo-[c]furanyl, 1,3-dihydro-2,1-benzisoxazolyl,dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl),2,3-dihydropyrrolo[2,3-b]pyridinyl, dioxolanyl, dioxanyl,hexahydropyrimidinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl,imidazo[2,3-b]thiazolyl, indanyl, indazolyl, indenyl, indolinyl,indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiochromanyl, ketopiperidinyl (e.g.2-ketopiperidinyl, 3-ketopiperidinyl or 4-ketopiperidinyl), morpholinyl,napthalenyl (e.g. 1,2,3,4-tetrahydronaphthyl), naphtho[1,2-b]furanyl,naphthyridinyl (including 1,6-naphthyridinyl or, particularly,1,5-naphthyridinyl and 1,8-naphthyridinyl), 1,2- or 1,3-oxazinanyl,oxazolidinyl, phenazinyl, phenothiazinyl, phenyl, phthalazinyl,piperidinyl, piperazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyridazinyl, pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl),pyridinonyl (such as 5-1H-pyridin-2-onyl, particularly,1-1H-pyridin-2-onyl, 3-1H-pyridin-2-onyl, 4-1H-pyridin-2-onyl,6-1H-pyridin-2-onyl (wherein 1-, 3-, 4- and 6-refer to the point ofattachment of the 1H-pyridin-2-onyl group to the rest of the molecule),or, particularly, 1H-pyridin-4-onyl), pyrimidinyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[5,1-b]pyridinyl,pyrrolo[2,3-c]pyridinyl, quinazolinyl, quinolinyl, quinolizinyl,quinoxalinyl, 4,5,6,7-tetrahydrobenzimidazolyl,4,5,6,7-tetrahydrobenzopyrazolyl, 5,6,7,8-tetrahydrobenzo-[e]pyrimidine,tetrahydroisoquinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl),tetrahydropyranyl, tetrahydropyridinyl (e.g3,4,5,6-tetrahydropyridinyl), 1,2,3,4-tetrahydropyrimidinyl,3,4,5,6-tetrahydropyrimidinyl, tetrahydrothiophenyl,thieno[5,1-c]pyridinyl, thiochromanyl, thiophenetyl, thiomorpholinyl,triazinanyl, 1,3,4-triazolo[2,3-b]pyrimidinyl, or xanthenyl and thelike.

Further, definitions of B that may be mentioned include2-azabicyclo[4.1.0]heptanyl, 1-azabicyclo-[2.2.2]octanyl, azepinyl,azetidinyl, aziridinyl, benzimidazolyl, benzisothiazolyl,benzisoxazolyl, benzodioxanyl, benzodioxolyl, benzofurazanyl,benzo[c]isoxazolidinyl, benzomorpholinyl, 2,1,3-benzoxadiazolyl,benzoxazinyl (including 3,4-dihydro-2H-1,4-benzoxazinyl),benzoxazolidinyl, benzoxazolyl, benzopyrazolyl, benzo[e]pyrimidine,2,1,3-benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl,chromanyl, chromenyl, cinnolinyl, cyclohexyl, cyclohexenyl, cyclopentyl,cyclopentenyl, cyclopropyl, cyclopropenyl, decahydroisoquinolenyl,2,3-dihydrobenzimidazolyl, diazepinyl, dihydrofuranyl (e.g.2,3-dihydrofuranyl, 2,5-dyhdrofuranyl), 2,3-dihydrobenzo[b]furanyl,1,3-dihydrobenzo-[c]furanyl, dihydropyranyl (e.g. 3,4-dihydropyranyl,3,6-dihydropyranyl), 4,5-dihydro-1H-maleimido,1,3-dihydro-2,1-benzisoxazolyl 2,3-dihydropyrrolo[2,3-b]pyridinyl,dioxanyl, dioxolanyl, furazanyl, hexahydropyrimidinyl, hydantoinyl,imidazolyl, imidazo[1,2-a]pyridinyl, imidazo[2,3-b]thiazolyl, indanyl,indenyl, indolinyl, isobenzofuranyl, isochromanyl, isoindolinyl,isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolyl,isoxazolidinyl, ketopiperidinyl (e.g. 2-ketopiperidinyl,3-ketopiperidinyl or 4-ketopiperidinyl), morpholinyl, napthalenyl (e.g.1,2,3,4-tetrahydronaphthyl), naphthyridinyl (including1,6-naphthyridinyl or, particularly, 1,5-naphthyridinyl and1,8-naphthyridinyl), oxadiazolyl, 1,2- or 1,3-oxazinanyl, oxazolidinyl,oxazolyl, piperidinyl, piperazinyl, phthalazinyl, pteridinyl, purinyl,pyranyl, pyridazinyl, pyrrolidinonyl, pyrrolinyl (e.g. 3-pyrrolinyl),pyrrolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[5,1-b]pyridinyl,pyrrolo[2,3-c]pyridinyl, quinazolinyl, quinolinyl, quinolizinyl,quinoxalinyl, sulfolanyl, 3-sulfolenyl, tetrahydrofuranyl,tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl,1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl,tetrahydrothiophenyl, 4,5,6,7-tetrahydrobenzimidazolyl,4,5,6,7-tetrahydrobenzopyrazolyl, 5,6,7,8-tetrahydrobenzo-[e]pyrimidine,tetrahydroisoquinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl),tetramethylenesulfoxide, tetrazolyl, thiazolidinyl, thiazolyl, thienyl,thieno[5,1-c]pyridinyl, thiochromanyl, thiophenetyl, thiomorpholinyl,triazinanyl, triazoly, 1,3,4-triazolo[2,3-b]pyrimidinyl or moreparticularly, benzofuranyl, furanyl, indazolyl, indolyl, pyrazinyl,pyrazolyl, pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl),pyridinonyl, pyrimidinyl, pyrrolo[1,5-a]pyridinyl, or phenyl and thelike.

Unless otherwise stated, the term “aryl” when used herein includes C₆₋₁₄(such as C₆₋₁₀) aryl groups. Such groups may be monocyclic, bicyclic ortricyclic and have between 6 and 14 ring carbon atoms, in which at leastone ring is aromatic. The point of attachment of aryl groups may be viaany atom of the ring system. However, when aryl groups are bicyclic ortricyclic, they are linked to the rest of the molecule via an aromaticring. C₆₋₁₄ aryl groups include phenyl, naphthyl and the like, such as1,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl. Embodimentsof the invention that may be mentioned include those in which aryl isphenyl.

Het¹ to Het⁴ groups may be fully saturated, partly unsaturated, whollyaromatic or partly aromatic in character. Values of Het¹ to Het⁴ groupsthat may be mentioned include acridinyl, 1-azabicyclo-[2.2.2]octanyl,azetidinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl,benzodioxanyl, benzodioxepanyl, benzodioxepinyl, benzodioxolyl,benzofuranyl, benzofurazanyl, benzo[c]isoxazolidinyl, benzomorpholinyl,2,1,3-benzoxadiazolyl, benzoxazinyl (including3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolidinyl, benzoxazolyl,benzopyrazolyl, benzo[e]pyrimidine, 2,1,3-benzothiadiazolyl,benzothiazolyl, benzothienyl, benzotriazolyl, carbazolyl, chromanyl,chromenyl, cinnolinyl, 2,3-dihydrobenzimidazolyl,2,3-dihydrobenzo[b]furanyl, 1,3-dihydrobenzo-[c]furanyl,1,3-dihydro-2,1-benzisoxazolyl 2,3-dihydropyrrolo[2,3-b]pyridinyl,dioxanyl, furanyl, furazanyl, hexahydropyrimidinyl, hydantoinyl,imidazolyl, imidazo[1,2-a]pyridinyl, imidazo[2,3-b]thiazolyl, indazolyl,indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl,isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl,isoxazolidinyl, isoxazolyl, maleimido, morpholinyl,naphtho[1,2-b]furanyl, naphthyridinyl (including 1,6-naphthyridinyl or,particularly, 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl,1,2- or 1,3-oxazinanyl, oxazolyl, phenazinyl, phenothiazinyl,phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl,pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolo[2,3-b]pyridinyl,pyrrolo[5,1-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolyl,quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, sulfolanyl,3-sulfolenyl, 4,5,6,7-tetrahydrobenzimidazolyl,4,5,6,7-tetrahydrobenzopyrazolyl, 5,6,7,8-tetrahydrobenzo-[e]pyrimidine,tetrahydrofuranyl, tetrahydroisoquinolinyl (including1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl),tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl,tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and5,6,7,8-tetrahydroquinolinyl), thiadiazolyl, thiazolidinyl, thiazolyl,thienyl, thieno[5,1-c]pyridinyl, thiochromanyl, thiophenetyl, triazolyl,1,3,4-triazolo[2,3-b]pyrimidinyl, xanthenyl and the like.

Het^(a) and Het^(c) to Het^(e) groups may be fully saturated, partlyunsaturated, wholly aromatic or partly aromatic in character. Het^(a)groups that may be mentioned include azetidinyl, aziridinyl, dioxanyl,furanyl, furazanyl, hexahydropyrimidinyl, hydantoinyl, imidazolyl,maleimido, morpholinyl, oxadiazolyl, 1,2- or 1,3-oxazinanyl, oxazolyl,piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl,pyrrolyl, sulfolanyl, 3-sulfolenyl, tetrahydrofuranyl,tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl,1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl,thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiophenetyl, triazolyland the like.

Het^(b) groups may be fully saturated, partly unsaturated, whollyaromatic or partly aromatic in character. Het^(b) groups that may bementioned include dioxanyl, furanyl, furazanyl, hexahydropyrimidinyl,hydantoinyl, imidazolyl, maleimido, morpholinyl, oxadiazolyl, 1,2- or1,3-oxazinanyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinonyl,pyrrolidinyl, pyrrolinyl, pyrrolyl, sulfolanyl, 3-suffolenyl,tetrahydrofuranyl, tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl,1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl,thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiophenetyl, triazolyland the like.

Substituents on heterocyclic (Het^(A), Het^(B), Het¹ to Het⁴, Het^(a) toHet^(e)) groups may, where appropriate, be located on any atom in thering system including a heteroatom. The point of attachment ofheterocyclic (Het^(A), Het^(B), Het¹ to Het⁴, Het^(a) to Het^(e)) groupsmay be via any atom in the ring system including (where appropriate) aheteroatom (such as a nitrogen atom), or an atom on any fusedcarbocyclic ring that may be present as part of the ring system.Heterocyclic (Het^(A), Het^(B), Het¹ to Het⁴, Het^(a) to Het^(e)) groupsmay also be in the N- or S-oxidised form.

Embodiments of the invention that may be mentioned include those inwhich L¹ and L² independently represent a direct bond, O, NR^(3a),S(O)_(p), CH₂ or C(O).

In certain embodiments of the invention, L¹ and L² represent singlebonds, R¹ represents H, and the compound of formula I may be representedas a compound of formula A1.

wherein A represents Cy^(AA) or Het^(AA);

Cy^(AA) represents a 6-membered aromatic, fully saturated or partiallyunsaturated carbocyclic ring system, which Cy^(AA) group is substituted,in the 3-position relative to the point of attachment to the triazinering, with a R^(4a) substituent and is optionally substituted by one ormore additional R^(4a) substituents;

Het^(AA) represents a 6-membered heterocyclic group that may bearomatic, fully saturated or partially unsaturated, and which containsone or more heteroatoms selected from O, S and N, and which Het^(AA)group is substituted, in the 3-position relative to the point ofattachment to the triazine ring, with a R substituent and is optionallysubstituted by one or more additional R^(4b) substituents;

B represents a Cy^(BB) or Het^(BB);

Cy^(BB) represents phenyl optionally substituted by one or more R^(4c)substituents;

Het^(BB) represents a 6-membered aromatic heterocyclic group whichcontains one or more N atoms, and which Het^(BB) group is optionallysubstituted by one or more R^(4d) substituents;

R^(4a), R^(4b), R^(4c) and R^(4d) are as defined above in relation tocompounds of formula I.

Embodiments of the invention that may be mentioned include those thatrelate to compounds of formula I (or, particularly, formula A1) in whichA represents Cy^(AA), Het^(AA′), Het^(AA″) or Het^(AA′″), wherein:

Cy^(AA′) represents a 6-membered aromatic, fully saturated or partiallyunsaturated carbocyclic ring system, which Cy^(AA′) group issubstituted, in the 3-position relative to the point of attachment tothe triazine ring, with a R^(4a) substituent and is substituted in the4-position relative to the point of attachment to the triazine ring,with a OR⁸ substituent and is optionally further substituted by one ormore additional R^(4a) substituents;

Het^(AA′) represents a 6-membered heterocyclic group that may bearomatic, fully saturated or partially unsaturated, and which containsone or more heteroatoms selected from O, S and N, and which Het^(AA′)group is substituted, in the 3-position relative to the point ofattachment to the triazine ring, with a R^(4b) substituent and issubstituted, in the 4-position relative to the point of attachment tothe triazine ring, with a OR⁸ substituent, and is optionally furthersubstituted by one or more additional R^(4b) substituents;

Het^(AA″) represents a 6-membered heterocyclic group that may bearomatic, fully saturated or partially unsaturated, and which contains,in the 4-position relative to the point of attachment to the triazinering, a N-atom, and which group optionally contains one or more furtherheteroatoms selected from O, S and N, which Het^(AA″) group issubstituted, in the 3-position relative to the point of attachment tothe triazine ring, with a R^(4b) substituent and is optionallysubstituted by one or more additional R^(4b) substituents; and

Het^(AA′″) represents a 6-membered heterocyclic group that may bearomatic, fully saturated or partially unsaturated, and which containsone or more heteroatoms selected from O, S and N, which Het^(AA′″) groupis substituted, in the 3-position relative to the point of attachment tothe triazine ring, with a R^(4b) substituent and is substituted, in the4-position relative to the point of attachment to the triazine ring,with an oxo (═O) group, and is optionally further substituted by one ormore additional R^(4b) substituents (e.g. Het^(AA′″) represents a4-pyridon-1-yl optionally substituted by one or more R^(4b)substituents).

Further embodiments of the invention that may be mentioned include thosethat relate to compounds of formula I (or, particularly, formula A1) inwhich:

when A represents Cy^(AA) or Cy^(AA′), that 6-membered carbocyclic ringis further substituted, in the 5-position relative to the point ofattachment to the triazine ring, with a R^(4a) substituent; or

when A represents Het^(AA), Het^(AA′), Het^(AA″) or Het^(AA′″), that6-membered heterocyclic ring is further substituted, in the 5-positionrelative to the point of attachment to the triazine ring, with a R^(4b)substituent.

Still further embodiments of the invention that may be mentioned includethose that relate to compounds of formula I (or, particularly, formulaA1) in which:

-   (1) Het^(BB) represents a 6-membered aromatic heterocyclic group    which contains 3, 2 or, particularly, 1 N atoms, and which Het^(BB)    group is optionally substituted by one or more R^(4d) substituents;-   (2) B represents Cy^(BB);-   (3) Cy^(BB) represents phenyl optionally substituted by one or two    R^(4c) substituents;-   (4) Cy^(AA) represents phenyl substituted, in the 3-position    relative to the point of attachment to the triazine ring, with a    R^(4a) substituent, and optionally substituted by one or more    additional R^(4a) substituents:-   (5) Het^(AA) represents a 6-membered aromatic heterocyclic group    which contains one or more (e.g. 3, 2 or particularly 1) N atoms,    and which Het^(AA) group is substituted, in the 3-position relative    to the point of attachment to the triazine ring, with a R^(4b)    substituent and is optionally substituted by one or more additional    R^(4b) substituents;-   (6) B represents a pyrimidinyl ring or, particularly, a phenyl or    pyridinyl (e.g. a pyridin-4-yl) ring, which ring is optionally    substituted by one or more R^(4c) or R^(4d) substituents;-   (7) R^(4c) and R^(4d) represent, independently at each occurrence,    -   (a) halo (e.g. chloro or, particularly, fluoro),    -   (b) CN,    -   (c) C₁₋₆ alkyl optionally substituted by one or more        substituents selected from halo and OR^(5a), or    -   (d) OR⁸;-   (8) A represents a Cy^(AA) or Het^(AA) group that is unsubstituted    in the ortho-positions relative to the point of attachment to the    triazine ring;-   (9) R^(4a) and R^(4b) represent, independently at each occurrence,    -   (a) halo,    -   (b) CN,    -   (c) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, which latter three        groups are optionally substituted by one or more substituents        selected from halo, nitro, CN, C₁₋₄ alkyl, (which latter group        is optionally substituted by one or more substituents selected        from OH, ═O, halo), OR^(5a), N(R^(5g))(R^(5h)),        B¹—C(G¹)-B²—R^(5i), aryl and Het¹,    -   (d) Cy³, which Cy³ group is optionally substituted by one or        more substituents selected from halo, nitro, CN, C₁₋₄ alkyl,        (which latter group is optionally substituted by one or more        substituents selected from OH, ═O, halo), OR^(6a),        N(R^(6g))(R^(6h)), B³—C(G¹)-B⁴—R^(6i), aryl and Het²,    -   (e) Het^(a), which Het^(a) group is optionally substituted by        one or more substituents selected from halo, nitro, CN, C₁₋₄        alkyl, (which latter group is optionally substituted by one or        more substituents selected from OH, ═O, halo), OR^(7a),        N(R^(7g))(R^(7h)), B⁵—C(G¹)-B⁶—R^(7i), aryl and Het³,    -   (f) OR⁸,    -   (g) S(O)_(r)R^(9a),    -   (j) N(R^(9f))(R^(9g)),    -   (k) B⁷—C(G¹)-B⁸—R^(9h),    -   (l) ═O,    -   or when two R^(4a) or R^(4b) groups are attached to the same        carbon atom in a non-aromatic portion of a Cy¹, Cy^(AA), Het^(A)        or Het^(AA) group, they may form, together with the carbon atom        to which they are attached, a saturated or unsaturated 3 to        6-membered ring, which ring optionally contains one to three        heteroatoms selected from O, S and N, and which ring is        optionally substituted by one or more R^(9i) substituents;

Still further embodiments of the invention that may be mentioned includethose that relate to compounds of formula I (or, particularly, formulaA1) in which R^(4a) to R^(4b) represent, independently at eachoccurrence,

-   -   (a) halo,    -   (b) CN,    -   (c) C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, which latter three        groups are optionally substituted by one or more substituents        selected from halo, C₁₋₄ alkyl and OR^(5a),    -   (d) Cy³,    -   (e) Het^(a),    -   (f) OR⁸, wherein R⁸ represents H or C₁₋₄ alkyl optionally        substituted by one or more halo atoms;    -   (g) S(O)_(f)R^(9a), wherein R^(9a) represents C₁₋₃ alkyl        optionally substituted by one or more halo atoms;    -   (h) N(R^(9f))(R^(9g)), wherein R^(9f) and R^(9g) independently        represent C₁₋₃ alkyl optionally substituted by one or more halo        atoms;    -   (i) B⁷—C(G¹)-B⁶—R^(9h), wherein R^(9h) represents C₁₋₃ alkyl        optionally substituted by one or more halo atoms;    -   (j) ═O,    -   or when two R^(4a) or R^(4b) groups are attached to the same        carbon atom in a non-aromatic portion of a Cy¹, Cy^(AA), Het^(A)        or Het^(AA) group, they may form, together with the carbon atom        to which they are attached, a saturated 3 to 6-membered ring.

Still further embodiments of the invention that may be mentioned includethose that relate to compounds of formula I (or, particularly, formulaA1) in which B represents a Cy^(BB) or Het^(BB) group (e.g. phenyl),which group is either unsubstituted or is substituted by one or moresubstituents selected from fluoro, CN, OR⁸ or C₁₋₆ alkyl optionallysubstituted by one or more substituents selected from halo and OR^(5a),wherein R^(5a) and R⁶ are as hereinbefore defined.

In particular embodiments, B represents a Cy^(BB) or Het^(BB) group(e.g. phenyl), which group is either unsubstituted or is substituted byone or more fluoro atoms (e.g. at the 4-position relative to the pointof attachment to the triazine ring) only.

In other embodiments of the invention, R^(4a) is (or R^(4a) and R^(4b)are) as defined above except that it does (they do) not represent OR⁸ inwhich R⁸ represents CH₃. In such circumstances, R^(4a) (or R^(4a) andR^(4b)) may, for example, (independently) represent, at each occurrence,halo, OH, N(H)—C(O)—C₁₋₃ alkyl or C₁₋₃ alkyl optionally substituted byone or more fluoro atoms.

In certain embodiments of the invention, the compound of formula I maybe represented as a compound of formula Ix, Iy or Iz,

respectively, wherein:

-   -   A′ represents Cy^(1′) or Het^(A′).    -   Cy^(1′) represents a 6-membered aromatic, fully saturated or        partially unsaturated carbocyclic ring system comprising one,        two or three rings, which Cy^(1′) group is substituted, in the        4-position relative to the point of attachment to L¹, with a OR⁸        substituent and is optionally further substituted by one or more        R^(4a) substituents;    -   Het^(A′) represents a 6-membered heterocyclic group that may be        aromatic, fully saturated or partially unsaturated, and which        contains one or more heteroatoms selected from O, S and N, which        heterocyclic group may comprise one, two or three rings and        which Het^(A′) group is substituted, in the 4-position relative        to the point of attachment to L¹, with a OR⁸ substituent and is        optionally further substituted by one or more R^(4b)        substituents;    -   (e.g. A′ represents phenyl which group is substituted, in the        4-position relative to the point of attachment to L¹, with a OR⁸        substituent and is optionally further substituted by one or more        R^(4a) substituents);    -   A″ represents Het^(A″);    -   Het^(A″) represents a 6-membered heterocyclic group that may be        aromatic, fully saturated or partially unsaturated, and which        contains, in the 4-position relative to the point of attachment        to L¹, a N-atom, and which group optionally contains one or more        further heteroatoms selected from O, S and N, which Het^(A″)        group is optionally substituted by one or more R^(4b)        substituents;    -   (e.g. A″ represents 6-membered aromatic heterocyclic group (e.g.        pyridyl) that contains, in the 4-position relative to the point        of attachment to L¹, a N atom, which heterocyclic group is        optionally substituted by one or more R^(4b) substituents);    -   A′″ represents Het^(A′″);    -   Het^(A′″) represents a 6-membered heterocyclic group that may be        aromatic, fully saturated or partially unsaturated, and which        contains one or more heteroatoms selected from O, S and N, which        Het^(A′″) group is substituted, in the 4-position relative to        the point of attachment to L¹, an oxo (═O) group, and is        optionally further substituted by one or more R^(4b)        substituents;    -   (e.g. A′″ represents 4-pyridon-1-yl optionally substituted by        one or more R^(4b) substituents); and    -   B, L¹, L², R¹, R^(4a), R^(4b) and R⁶ are as defined above in        relation to compounds of formula I (or A1).

Embodiments of the invention that may be mentioned include those thatrelate to compounds of formula I in which at least one of L¹ and L²represents a direct bond, while the other may represent CH═CH or,particularly, a direct bond, O, NR^(3a), S(O)_(p), CH₂ or C(O) (e.g. atleast one of L¹ and L² represents a direct bond, and the otherrepresents CH═CH or, particularly, C(O) or, more particularly, a directbond, O, NR^(3a) or S(O)_(p)).

Thus, in an embodiment of the invention, L¹ and L² are both directbonds.

Embodiments of the invention that may be mentioned include those thatrelate to compounds of formula I wherein L¹ represents a direct bond andL² is selected from CH═CH or, particularly, a O, NR^(3a), S(O)_(p), CH₂and C(O) (e.g. L¹ represents a direct bond and L² is selected from O,CH₂ or C(O)).

Further embodiments of the invention that may be mentioned include thosethat relate to compounds of formula I wherein L² represents a directbond and L¹ is selected from CH═CH or, particularly, O, NR^(3a),S(O)_(p), CH₂ and C(O) (e.g. L² represents a direct bond and L¹ isselected from O, CH₂ or C(O)).

Embodiments of the invention that may be mentioned include those thatrelate to compounds of formula I in which:

-   (1) R¹ represents H or C₁₋₃ alkyl, which latter group is optionally    substituted by one or more of halo, OR^(2a) or NR^(2b)R^(2c)    -   (e.g. R¹ represents H or C₁₋₃ alkyl, which latter group is        optionally substituted by one or more of halo or NR^(2b)R^(2c)        or, particularly, R¹ represents H or C₁₋₂ alkyl, which latter        group is optionally substituted by one or more of halo or        NR^(2b)R^(2c));-   (2) L¹ and L² independently represent CH═CH or, particularly,    NR^(3a), S(O)_(p), or, more particularly, CH₂, or, still more    particularly, a direct bond, O, or C(O);-   (3) R^(2a), R^(2b) and R^(2c) and R^(3a) represents H or C₁₋₃ alkyl,    which latter group is optionally substituted by one or more halo    atoms    -   (e.g. R^(2a) represents C₁₋₃ alkyl, which group is optionally        substituted by one or more halo atoms; R^(2b) and R^(2c)        independently represent H or methyl, which latter group is        optionally substituted by one or more halo atoms; and R^(3a)        represents H or C₁₋₃ alkyl, which latter group is optionally        substituted by one or more halo atoms);-   (4) Cy¹ represents a 5- to 13-membered (e.g. 5- to 10- or more    particularly 6- to 10-membered) aromatic, fully saturated or    partially unsaturated carbocyclic ring system comprising one to    three (e.g. one or two) rings, which Cy¹ group is optionally    substituted by one or more R^(4a) substituents;-   (5) Het^(A) represents a 5- to 13-membered (e.g. 5- to 10- or more    particularly 6- to 10-membered) heterocyclic group that may be    aromatic, fully saturated or partially unsaturated, and which    contains one or more heteroatoms selected from O, S and N, which    heterocyclic group may comprise one to three (e.g. one or two) rings    and which Het^(A) group is optionally substituted by one or more    R^(4b) substituents;-   (6) Cy² represents a 5- to 10-membered (e.g. 5- to 9-membered or,    particularly, 6- to 9-membered) aromatic, fully saturated or    partially unsaturated carbocyclic ring system comprising one or two    rings, which Cy² group is optionally substituted by one or more    R^(4c) substituents;-   (7) Het^(B) represents a 5- to 10-membered (e.g. 5- to 9-membered    or, particularly, 6- to 9-membered) heterocyclic group that may be    aromatic, fully saturated or partially unsaturated, and which    contains one or more heteroatoms selected from O, S and N, which    heterocyclic group may comprise one to three (e.g. one or two) rings    and which Het^(B) group is optionally substituted by one or more    R^(4d) substituents;-   (8) R^(4a) to R^(4d) represent, independently at each occurrence,    -   halo,    -   CN,    -   C₁₋₆ alkyl (e.g. C₂₋₆ alkyl), C₂₋₆ alkenyl, C₂₋₆ alkynyl (which        latter three groups are optionally substituted by one or more        substituents selected from halo, nitro, CN, C₁₋₃ alkyl, C₂₋₃        alkenyl, C₂₋₃ alkynyl (which latter three groups are optionally        substituted by one or more substituents selected from OH, ═O,        halo, C₁₋₃ alkyl and C₁₋₃ alkoxy). OR^(5a), S(O)_(q)R^(5b),        S(O)₂N(R^(5c))(R^(5d)), N(R^(5e))S(O)₂R^(5f), N(R^(5g))(R^(5h)),        B¹—C(G¹)-B²—R^(5i), aryl and Het¹,    -   Cy³, which Cy³ group is optionally substituted by one or more        substituents selected from halo, nitro, CN, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl (which latter three groups are optionally        substituted by one or more substituents selected from OH, ═O,        halo, C₁₋₄ alkyl and C₁₋₄ alkoxy), OR^(6a), S(O)_(q)R^(6b),        S(O)₂N(R^(6c))(R^(6d)), N(R^(6e))S(O)₂R^(6f), N(R^(6g))(R^(6h)),        B³—C(G¹)-B⁴—R^(6i), aryl and Het²,    -   Het^(a), which Het^(a) group is optionally substituted by one or        more substituents selected from halo, nitro, CN, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl (which latter three groups are        optionally substituted by one or more substituents selected from        OH, ═O, halo, C₁₋₄ alkyl and C₁₋₄ alkoxy), OR^(7a),        S(O)_(q)R^(7b), S(O)₂N(R^(7c))(R^(7d)), N(R^(7e))S(O)₂R^(7f),        N(R^(7g))(R^(7h)), B⁵—C(G¹)-B⁶—R^(7i), aryl and Het³,    -   OR⁸,    -   S(O)_(r)R^(9a),    -   S(O)₂N(R^(9b))(R^(9c)),    -   N(R^(9c))S(O)₂R^(9e),    -   N(R^(9f))(R^(9g))    -   B⁷—C(G¹)-B⁸—R^(9h),    -   ═O,    -   ═S,    -   or when two R^(4a), R^(4b), R^(4c) or R^(4d) groups are attached        to the same carbon atom in a non-aromatic portion of a Cy¹,        Het^(A), Cy² or Het^(B) group, they may form, together with the        carbon atom to which they are attached, a saturated or        unsaturated 3 to 6-membered ring, which ring optionally contains        one to three heteroatoms selected from O, S and N, and which        ring is optionally substituted by one or more R^(9i)        substituents;-   (9) G¹ represents, independently at each occurrence, O or S;-   (10) R⁸ represents, independently at each occurrence,    -   H,    -   Cy³, Het^(a), aryl^(a), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₃₋₆ cycloalkyl, which latter seven groups are optionally        substituted by one or more substituents selected from halo, —CN,        C₃₋₆ cycloalkyl, aryl, Het⁴, —C(O)OR¹⁰, —C(O)R¹¹ and        —C(O)N(R^(N1))(R^(N2)), S(O)_(r)R^(9aa),        S(O)₂N(R^(9ba))(R^(9ca)), N(R^(9da))S(O)₂R^(9ea) and        N(R^(9fa))(R^(9ga));-   (11) Cy³ represents, independently at each occurrence, C₃₋₆    cycloalkyl, C₃₋₆ cycloalkenyl or phenyl;-   (12) Het^(a) represents, independently at each occurrence, a 4- to    6-membered heterocyclic ring that may be aromatic, fully saturated    or partially unsaturated and which contains one or more heteroatoms    selected from O, S and N;-   (13) R¹⁰ and R¹¹ independently represent    -   H,    -   C₁₋₃ alkyl optionally substituted by one or more substituents        selected from halo, aryl, —N(R^(N3))(R^(N4)) and —OR^(a),    -   phenyl (which latter group is optionally substituted by one or        more substituents selected from OH, halo, C₁₋₄ alkyl and C₁₋₄        alkoxy) or    -   C₃₋₆ cycloalkyl (which latter group is optionally substituted by        one or more substituents selected from OH, ═O, halo, C₁₋₄ alkyl        and C₁₋₄ alkoxy);-   (14) B¹ to B⁸ independently represent, at each occurrence, O or,    particularly, a direct bond or N(R^(N3));-   (15) each aryl^(a) independently represents a C₆₋₁₀ carbocyclic    aromatic group (e.g. phenyl), which group may comprise one or two    rings:-   (16) each aryl independently represents a C₆₋₁₀ carbocyclic aromatic    group (e.g. phenyl), which group may comprise one or two rings and    may be substituted by one or more substituents selected from    -   halo,    -   C₁₋₆ alkyl, which latter group is optionally substituted by one        or more substituents selected from halo, —N(R^(N4))(R^(N5)) and        —OR^(a), and    -   —OR^(a);-   (17) Het¹ to Het⁴ independently represent 5- to 13-membered    heterocyclic groups containing one or more heteroatoms selected from    O, S and N, which heterocyclic groups may comprise one, two or three    rings and may be substituted by one or more substituents selected    from    -   halo,    -   C₁₋₆ alkyl, which latter group is optionally substituted by one        or more substituents selected from halo, —N(R^(N6))(R^(N7)) and        —OR^(a), and —OR^(a);-   (18) R^(N1) to R^(N7) independently represent    -   H,    -   C₁₋₃ alkyl or C₃₋₅ cycloalkyl, which latter two groups are        optionally substituted by one or more substituents selected from        halo and —OR^(a);-   (19) R^(a) represents, independently at each occurrence,    -   H,    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₄₋₆        cycloalkenyl (which latter five groups are optionally        substituted by one or more substituents selected from halo,        nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl (which latter three groups are optionally substituted        by one or more substituents selected from OH, ═O, halo, C₁₋₄        alkyl and C₁₋₄ alkoxy), OR^(12a), S(O)_(q)R^(12b),        S(O)₂N(R^(12c))(R^(12d)), N(R^(12e))S(O)₂R^(12f),        N(R^(12g))(R^(12h)), B⁹—C(G²)-B¹⁰—R^(12i), aryl¹ and Het^(b),        and which C₃₋₆ cycloalkyl or C₄₋₆ cycloalkenyl groups may        additionally be substituted by ═O),    -   S(O)_(r)R^(13a),    -   S(O)₂N(R^(13b))(R^(13c)) or    -   C(O)—B¹³—R^(13d);-   (20) R^(5a) to R^(5i), R^(6a) to R^(6i), R^(7a) to R^(7i), R^(9a) to    R^(9i), R^(9aa) to R^(9ga), R^(12a) to R^(12i) and R^(13a) to    R^(13d) independently represent, at each occurrence,    -   H,    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl (which latter three        groups are optionally substituted by one or more substituents        selected from halo, OH and C₁₋₄ alkoxy),    -   C₃₋₆ cycloalkyl or C₄₋₈ cycloalkenyl (which latter two groups        are optionally substituted by one or more substituents selected        from halo, OH, ═O, C₁₋₆ alkyl and C₁₋₆ alkoxy),    -   Het^(d);-   (21) G² represents, independently at each occurrence, O or S;-   (22) R^(5aa) to R^(5aj) independently represent at each occurrence,    -   H,    -   C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl which latter three groups        are optionally substituted by one or more substituents selected        from halo, nitro, CN, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl        (which latter three groups are optionally substituted by one or        more substituents selected from OH, ═O, halo, C₁₋₄ alkyl and        C₁₋₄ alkoxy),    -   C₃₋₅ cycloalkyl, or C₄₋₅ cycloalkenyl (which latter two groups        are optionally substituted by one or more substituents selected        from halo, OH, ═O, C₁₋₄ alkyl and C₁₋₄ alkoxy),    -   Het^(a);-   (23) B⁹ to B¹³ independently represent a direct bond or N(R^(N8));-   (24) aryl¹ represents, independently at each occurrence, phenyl or    naphthyl, which may be substituted by one or more substituents    selected from    -   halo,    -   C₁₋₃ alkyl, which letter group is optionally substituted by one        or more substituents selected from halo, —N(R^(N10))(R^(N11))        and C₁₋₄ alkoxy (which latter substituent is optionally        substituted by one or more halo atoms), and    -   C₁₋₄ alkoxy (which latter substituent is optionally substituted        by one or more halo atoms);-   (25) R^(N8), R^(N10) and R^(N11) independently represent    -   H,    -   C₁₋₃ alkyl or C₃₋₃ cycloalkyl, which latter two groups are        optionally substituted by one or more halo atoms;-   (26) Het^(b) represents a heterocyclic group selected from dioxanyl,    furanyl, furazanyl, hexahydropyrimidinyl, hydantoinyl, imidazolyl,    maleimido, morpholinyl, oxadiazolyl, 1,2- or 1,3-oxazinanyl,    oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl,    pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl,    pyrrolinyl, pyrrolyl, sulfolanyl, 3-sulfolenyl, tetrahydrofuranyl,    tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl,    1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl,    thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiophenetyl,    triazolyl, which heterocyclic group may be substituted by one or    more substituents selected from halo, ═O and C₁₋₆ alkyl;-   (27) Het^(c) to Het^(e) independently represent, a 4- to 6-membered    heterocyclic ring that may be aromatic, fully saturated or partially    unsaturated and which contains one or more heteroatoms selected from    O, S and N, which Het^(c) to Het^(e) groups are optionally    substituted by one or more substituents selected from halo, nitro,    CN, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl (which latter three    groups are optionally substituted by one or more substituents    selected from OH, ═O, halo, C₁₋₄ alkyl and C₁₋₄ alkoxy).

Embodiments of the invention that may be mentioned include those thatrelate to compounds of formula I in which:

-   (1) Cy¹ represents a 5- to 10-membered (e.g. 6- to 10-membered)    aromatic, fully saturated or partially unsaturated carbocyclic ring    system comprising one or two rings, which Cy¹ group is optionally    substituted by one or more R^(4a) substituents;-   (2) Het^(A) represents a 5- to 10-membered (e.g. 6- to 10-membered)    heterocyclic group that may be aromatic, fully saturated or    partially unsaturated, and which contains one or more heteroatoms    selected from O, S and N, which heterocyclic group may comprise one    or two rings and which Het^(A) group is optionally substituted by    one or more R^(4b) substituents;-   (3) B represents a group, selected from 2-azabicyclo[4.1.0]heptanyl,    1-azabicyclo[2.2.2]octanyl, benzimidazolyl, benzisothiazolyl,    benzisoxazolyl, benzodioxanyl, benzodioxolyl, benzofurazanyl,    benzo[c]isoxazolidinyl, 2,1,3-benzoxadiazolyl, benzoxazolidinyl,    benzoxazolyl, benzopyrazolyl, 2,1,3-benzothiadiazolyl,    benzothiazolyl, benzothienyl, benzotriazolyl, cyclopentyl,    cyclohexyl, cyclopentenyl, cyclohexenyl, 2,3-dihydrobenzimidazolyl,    dihydrofuranyl (e.g. 2,3-dihydrofuranyl, 2,5-dyhdrofuranyl),    2,3-dihydrobenzo[b]furanyl, 1,3-dihydrobenzo-[c]furanyl,    dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl),    4,5-dihydro-1H-maleimido, 1,3-dihydro-2,1-benzisoxazolyl    2,3-dihydropyrrolo[2,3-b]pyridinyl, dioxanyl, dioxolanyl, furazanyl,    hexahydropyrimidinyl, hydantoinyl, imidazolyl,    imidazo[1,2-a]pyridinyl, imidazo[2,3-b]thiazolyl, indanyl, indenyl,    indolinyl, isobenzofuranyl, isoindolinyl, isoindolyl, isothiaziolyl,    isoxazolyl, isoxazolidinyl, ketopiperidinyl (e.g. 2-ketopiperidinyl,    3-ketopiperidinyl or 4-ketopiperidinyl), morpholinyl, oxadiazolyl,    1,2- or 1,3-oxazinanyl, oxazolidinyl, oxazolyl, piperidinyl (e.g.    piperidin-1-yl or, particularly, piperidin-2-yl, piperidin-3-yl,    piperidin-4-yl, piperidin-5-yl or piperidin-6-yl), piperazinyl,    phthalazinyl, pteridinyl, purinyl, pyranyl, pyridazinyl,    pyrrolidinonyl, pyrrolinyl (e.g. 3-pyrrolinyl), pyrrolyl,    pyrrolo[2,3-b]pyridinyl, pyrrolo[5,1-b]pyridinyl,    pyrrolo[2,3-c]pyridinyl, sulfolanyl, 3-sulfolenyl,    tetrahydrofuranyl, tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl,    1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl,    tetrahydrothiophenyl, 4,5,6,7-tetrahydrobenzimidazolyl,    4,5,6,7-tetrahydrobenzopyrazolyl, tetramethylenesulfoxide,    tetrazolyl, thiazolidinyl, thiazolyl, thienyl,    thieno[5,1-c]pyridinyl, thiophenetyl, triazinanyl, triazoly,    1,3,4-triazolo[2,3-b]pyrimidinyl, more particularly, benzofuranyl,    indazolyl, indolyl, pyrazinyl, pyrazolyl, pyridinyl (e.g.    2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyridinonyl, pyrimidinyl,    pyrrolo[1,5-a]pyridinyl, and, yet more particularly, phenyl, wherein    B is optionally substituted by one or more R^(4c) or R^(4d)    substituents, as appropriate (e.g. B represents a group selected    from benzofuranyl, furanyl, indazolyl, indolyl, pyrazinyl,    pyrazolyl, pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl),    pyridinonyl, pyrimidinyl, pyrrolo[1,5-a]pyridinyl, and phenyl,    wherein B is optionally substituted by one or more R^(4c) or R^(4d)    substituents, as appropriate).

In certain embodiments of the invention, B represents phenyl and thecompound of formula I may be represented as a compound of formula Ia,

wherein s represents 0 to 5 (e.g. 0 to 3 or, particularly, 0 to 2), andR^(4c), A, L¹, L² and R¹ are as defined above in relation to compoundsof formula I.

In certain embodiments of the invention, the compound of formula I maybe represented as a compound of formula Ixa, Iya or Iza,

respectively, wherein s1, s2 and s3 independently represent 0 to 5 (e.g.0 to 3 or, particularly, 0 to 2), and A′, A″, A′″, L¹, L², R^(4c) and R¹are as defined above in relation to compounds of formula I (or A1, orparticularly, Ix, Iy or Iz).

Embodiments of the invention that may be mentioned include those thatrelate to compounds of formula I (or A1 or, particularly, Ix, Iy Iz,Ixa, Iya and Iza or, more particularly, Ia) in which:

-   (1) R¹ represents H, CH₃, CF₃, CH₂F, CHF₂, CH₂CH₃, CH₂CF₃,    (CH₂)₂OCH₃, (CH₂)₂OCF₃, (CH₂)₃OCH₃, (CH₂)₃OCF₃, (CH₂)₂NH₂,    (CH₂)₂NH(CH₃), (CH₂)₂N(CH₃)₂, (CH₂)₃NH₂, (CH₂)₃NH(CH₃) or    (CH₂)₃N(CH₃)₂;-   (2) L¹ represents S, NH, CH═CH or, particularly, CH₂, a direct bond,    O, or C(O) (e.g. L¹ represents S, NH, CH═CH, a direct bond, O or    C(O) or, particularly, a direct bond, O or C(O) or, more    particularly, L¹ represents a direct bond);-   (3) L² represents CH₂, a direct bond, O, or C(O) (e.g. L² represents    a direct bond or O or, particularly, L² represents a direct bond);-   (4) R^(2a), R^(2b), R^(2c) and R^(3a) independently represent H,    CH₃, CF₃, CH₂F, CHF₂, CH₂CH₃ or CH₂CF₃    -   (e.g. R^(2a) represents CH₃, CF₃, CH₂F, CHF₂, CH₂CH₃ or CH₂CF₃        and R^(2b), R^(2c) and R^(3a) independently represent H, CH₃,        CF₃, CH₂F, CHF₂, CH₂CH₃ or CH₂CF₃);-   (5) A represents a group selected from    2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl,    6-oxa-9-azaspiro[4.5]decanyl, octahydroisoquinolin-(1H)-yl,    hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, pyridazinonyl or,    particularly, cyclopentyl, dihydrofuranyl (e.g 2,3-dihydrofuranyl,    2,5-dihydrofuranyl), 4,5-dihydro-1H-maleimido, dioxanyl, furazanyl,    hydantoinyl, imidazolyl, isoxazolyl, isoxazolidinyl, isothiaziolyl,    oxadiazolyl, oxazolyl, pyrazolyl, pyrrolinyl (e.g. 3-pyrrolinyl),    pyrrolyl, pyrrolidinonyl, sulfolanyl, 3-sulfolenyl,    tetrahydrofuranyl, tetramethylenesulfoxide, tetrazolyl,    thiadiazolyl, thiazolyl, thiazolidinyl, thienyl, triazolyl,    particularly 2-azabicyclo[4.1.0]heptanyl,    1-azabicyclo-[2.2.2]octanyl, benzimidazolyl, benzisothiazolyl,    benzisoxazolyl, benzodioxanyl, benzofuranyl, benzofurazanyl,    benzo[c]isoxazolidinyl, benzomorpholinyl, 2,1,3-benzoxadiazolyl,    benzoxazinyl (including 3,4-dihydro-2H-1,4-benzoxazinyl),    benzoxazolidinyl, benzopyrazolyl, benzo[e]pyrimidine,    2,1,3-benzothiadiazolyl, benzothiazolyl, benzothienyl,    benzotriazolyl, carbazolyl, chromanyl, chromenyl, cinnolinyl,    (1Z,2Z,4Z,6Z,8Z)-cyclodecapentaenyl, cyclohexyl, cyclopentenyl,    decahydroisoquinolenyl, 2,3-dihydrobenzimidazolyl,    1,3-dihydrobenzo-[c]furanyl, 1,3-dihydro-2,1-benzisoxazolyl,    dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl),    2,3-dihydropyrrolo[2,3-b]pyridinyl, dioxolanyl,    hexahydropyrimidinyl, imidazo[2,3-b]thiazolyl, indanyl, indazolyl,    indenyl, indolinyl, isobenzofuranyl, isochromanyl, isoindolinyl,    isoindolyl, isothiochromanyl, ketopiperidinyl (e.g.    2-ketopiperidinyl, 3-ketopiperidinyl or 4-ketopiperidinyl),    naphtho[1,2-b]furanyl, naphthyridinyl (including 1,6-naphthyridinyl    or, particularly, 1,5-naphthyridinyl and 1,8-naphthyridinyl), 1,2-    or 1,3-oxazinanyl, oxazolidinyl, phenazinyl, phenothiazinyl,    phthalazinyl, piperazinyl, pteridinyl, purinyl, pyranyl,    pyridazinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[5,1-b]pyridinyl,    pyrrolo[2,3-c]pyridinyl, quinazolinyl, quinolizinyl, quinoxalinyl,    4,5,6,7-tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzopyrazolyl,    5,6,7,8-tetrahydrobenzo-[e]pyrimidine, tetrahydroisoquinolinyl    (including 1,2,3,4-tetrahydroisoquinolinyl and    5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including    1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl),    tetrahydropyranyl, tetrahydropyridinyl (e.g.    3,4,5,6-tetrahydropyridinyl), 1,2,3,4-tetrahydropyrimidinyl,    3,4,5,6-tetrahydropyrimidinyl, tetrahydrothiophenyl,    thieno[5,1-c]pyridinyl, thiochromanyl, thiophenetyl, triazinanyl,    1,3,4-triazolo[2,3-b]pyrimidinyl, particularly, benzoxazolyl,    benzodioxolyl, 2,3-dihydrobenzo[b]furanyl, cyclohexyl, furanyl,    imidazo[1,2-a]pyridinyl, imidazo[1,5-e]pyridinyl, indolyl,    isoquinolinyl, morpholinyl, napthalenyl (e.g. 1-napthalenyl,    2-napthalenyl, 1,2,3,4-tetrahydronaphthyl), piperidinyl,    pyrimidinyl, pyrrolidinyl pyrrolo[1,5-a]pyridinyl, pyrazinyl,    pyridinonyl (such as 1-1H-pyridin-2-onyl, 3-1H-pyridin-2-onyl,    4-1H-pyridin-2-onyl, 6-1H-pyridin-2-onyl, or, particularly,    4-pyridinonyl), quinolinyl, more particularly, phenyl and pyridinyl    (e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), which cyclic system is    optionally substituted by one or more R^(4a) or R^(4b) substituents,    as appropriate:-   (6) R^(4a) to R^(4d) represent, independently at each occurrence,    -   halo,    -   CN,    -   C₁₋₆ alkyl (which latter group is optionally substituted by one        or more substituents selected from halo, nitro, CN, C₁₋₃ alkyl        (which latter group is optionally substituted by one or more        substituents selected from OH, ═O, halo, C₁₋₃ alkyl and C₁₋₃        alkoxy), OR⁵, S(O)_(q)R^(5b), S(O)₂N(R^(5c))(R^(5d)),        N(R^(5e))S(O)₂R^(5f), N(R^(5g))(R^(5h)) and B¹—C(G¹)-B²—R^(5i)),    -   Cy³, wherein Cy³ is a group selected from cyclobutyl,        cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl,        cyclopentenyl, cyclohexenyl, phenyl and, particularly,        cyclopropyl, which Cy³ group is optionally substituted by one or        more substituents selected from halo, nitro, CN, C₁₋₃ alkyl        (which group is optionally substituted by one or more        substituents selected from OH, ═O, halo, C₁₋₃ alkyl and C₁₋₃        alkoxy), OR^(6a), S(O)_(q)R^(6b), S(O)₂N(R^(6c))(Re),        N(R^(6d))S(O)₂R^(6f), N(R^(6g))(R^(6h)), B³—C(G¹)-B⁴—R^(6i) and        aryl,    -   Het^(a), wherein Het^(a) is a group selected from azetidinyl,        dihydrofuranyl (e.g. 2,3-dihydrofuranyl, 2,5-dihydrofuranyl),        dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl),        4,5-dihydro-1H-maleimido, dioxanyl, dioxolanyl, furanyl,        furazanyl, hexahydropyrimidinyl, hydantoinyl, imidazolyl,        isothiaziolyl, isoxazolidinyl, isoxazolyl, morpholinyl, 1,2- or        1,3-oxazinanyl, oxazolidinyl, oxazolyl, piperidinyl,        piperazinyl, pyranyl, pyrazinyl, pyridazinyl, pyrazolyl,        pyridinyl, pyrimidinyl, pyrrolinyl (e.g. 3-pyrrolinyl),        pyrrolyl, pyrrolidinyl, pyrrolidinonyl, 3-sulfolenyl,        sulfolanyl, tetrahydrofuranyl, tetrahydropyranyl,        tetrahydropyridinyl (e.g. 3,4,5,6-tetrahydropyridinyl),        1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl,        tetrahydrothiophenyl, tetramethylenesulfoxide, tetrazolyl,        thiadiazolyl, thiazolyl, thiazolidinyl, thienyl, thiophenethyl,        triazolyl and triazinanyl, which Het^(a) group is optionally        substituted by one or more substituents selected from halo,        nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl (which latter        three groups are optionally substituted by one or more        substituents selected from OH, ═O, halo, C₁₋₃ alkyl and C₁₋₃        alkoxy), OR^(7a), S(O)_(q)R^(7b), S(O)₂N(R^(7c))(R^(7d)),        N(R^(7e))S(O)₂R^(7i), N(R^(7g))(R^(7h)), B⁵—C(G)-B⁶—R^(7i) and        aryl,    -   OR⁸,    -   S(O)_(r)R^(9a),    -   S(O)₂N(R^(9b))(R^(9c)),    -   N(R^(9d))S(O)₂R^(9e),    -   N(R^(9f))(R^(9g))    -   B⁷—C(O)—B⁸—R^(9h),    -   B⁷—C(G¹)-B⁸—R^(9h),    -   ═O,    -   or when two R^(4a), R^(4b), R^(4c) or R^(4d) groups are attached        to the same carbon atom in a non-aromatic portion of a Cy¹,        Het^(A), Cy² or Het^(B) group, they may form, together with the        carbon atom to which they are attached, a saturated or        unsaturated 3 to 6-membered ring (e.g. dioxolanyl or        1,4-dioxanyl), which ring optionally contains one to three        heteroatoms selected from O, S and N, and which ring is        optionally substituted by one or more R^(9i) substituents;-   (7) G¹ represents, independently at each occurrence, O;-   (8) R⁸ represents, independently at each occurrence,    -   H,    -   C₁₋₆ alkyl, which latter group is optionally substituted by one        or more substituents selected from halo, —CN, C₃₋₆ cycloalkyl,        aryl, Het⁴, —C(O)OR¹⁰, —C(O)R¹¹ and —C(O)N(R^(N1))(R^(N2))    -   (e.g. R⁸ represents, independently at each occurrence, H or C₁₋₃        alkyl optionally substituted by fluoro (e.g. CH₂F, CHF₂,        CH₂CH₃CH₂CF₃, or particularly CH₃ or CF₃);-   (9) each aryl independently represents a phenyl group and is    optionally substituted by one or more substituents selected from    -   halo,    -   C₁₋₃ alkyl, which latter group is optionally substituted by one        or more substituents selected from halo, —N(R^(N4))(R^(N5)) and        —OR^(a), and    -   —OR^(a);-   (10) R^(a) represents independently at each occurrence,    -   H,    -   C₁₋₃ alkyl, (which latter group is optionally substituted by one        or more substituents selected from halo, OH and C₁₋₄ alkoxy) or    -   C₃₋₆ cycloalkyl (which latter group is optionally substituted by        one or more substituents selected from halo, OH, ═O, C₁₋₆ alkyl        and C₁₋₄ alkoxy).

In certain other embodiments of the invention, B represents phenyl andL² represents a direct bond and the compound of formula I may berepresented as a compound of formula Ib,

wherein R^(4c), A and L¹ are as defined above in relation to compoundsof formula I (or A1 or, particularly, Ia) and t represents 0 to 5 (e.g.from 0 to 3, or particularly from 0 to 2).

In certain embodiments of the invention, the compound of formula I maybe represented as a compound of formula Ixb, Iyb or Izb,

respectively, wherein t1, t2 and t3 independently represent 0 to 5 (e.g.0 to 3 or, particularly, 0 to 2), and A′, A″, A′″, R^(4c) and L¹ are asdefined above in relation to compounds of formula I (or A1 or,particularly, Ix, Iy, Iz, Ia, Ixa, Iya or Iza).

In certain embodiments of the invention, the compounds of formula I (orA1 or, particularly, Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb or, moreparticularly, Ia or Ib) are those in which:

-   (1) L¹ represents S, NH, CH═CH or, particularly, a direct bond or O    (e.g. L¹ represents a direct bond);-   (2) A represents a group selected from furanyl, pyrrolidinyl,    pyrazolyl, oxazolyl, particularly benzoxazolyl, benzodioxolyl,    2,3-dihydrobenzo[b]furanyl, cyclohexenyl, decahydroisoquinolenyl,    imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, indolyl,    isoquinolinyl, morpholinyl, napthalenyl (e.g. 1-napthalenyl,    2-napthalenyl, 1,2,3,4-tetrahydronaphthyl), piperidinyl,    pyrimidinyl, pyrrolo[1,5-a]pyridinyl, pyrazinyl, pyridinonyl (such    as 1-1H-pyridin-2-onyl, 3-1H-pyridin-2-onyl, 4-1H-pyridin-2-onyl,    6-1H-pyridin-2-onyl, or, particularly, 4-pyridinonyl), quinolinyl,    particularly, phenyl and pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl,    4-pyridinyl), which A group is optionally substituted by one or more    R^(4a) or R^(4b) substituents, as appropriate;-   (3) R^(4a) and R^(4b) represent, independently at each occurrence,    -   halo (e.g. iodo or, particularly, chloro, bromo or fluoro),    -   CN,    -   C₁₋₆ alkyl, (which latter group is optionally substituted by one        or more substituents selected from aryl or, particularly, halo        and OR^(5a)),    -   Cy³ wherein Cy³ is a group selected from cyclobutyl,        cyclopentyl, cyclohexyl phenyl and, particularly, cyclopropyl,        which Cy³ group is optionally substituted by one or more        substituents halo, nitro, CN, C₁₋₃ alkyl (which group is        optionally substituted by one or more substituents selected from        OH, ═O, halo, C₁₋₃ alkyl and C₁₋₃ alkoxy), OR^(6a),        S(O)_(q)R^(6b), S(O)₂N(R^(6c))(R^(6d)), N(R^(6e))S(O)₂R^(6f),        N(R^(6g))(R^(6h)), B³—C(G¹)-B⁴—R^(6i) and aryl,    -   Het^(B) wherein Het^(a) is a group selected from azetidine and,        particularly, dioxanyl and dioxolanyl which Het^(a) group is        optionally substituted by one or more substituents selected from        halo, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl (which        latter three groups are optionally substituted by one or more        substituents selected from OH, ═O, halo, C₁₋₃ alkyl and C₁₋₃        alkoxy), OR^(7a), S(O)_(q)R^(7b), S(O)₂N(R^(7c))(R^(7d)),        N(R^(7e))S(O)₂R^(7f), N(R^(7g))(R^(7h)), B⁵—C(G¹)-B⁶—R^(7i) and        aryl,    -   OR⁸,    -   S(O)_(r)R^(9a),    -   N(R^(9f))(R^(9g))    -   B⁷—C(G¹)-B⁸—R^(9h),    -   ═O,    -   or when two R^(4a) or R^(4b) groups are attached to the same        carbon atom in a non-aromatic portion of a Cy¹ or Het^(A) group,        they may form, together with the carbon atom to which they are        attached, a saturated or unsaturated 5-membered ring (e.g.        dioxolanyl), which ring optionally contains one to two        heteroatoms selected from O and N, and which ring is optionally        substituted by one or more R^(9i) substituents,    -   (e.g. R^(4a) or R^(4b) represents, independently at each        occurrence, CH₂F or, particularly, iodo, butyl, CH(CH₃)OH,        OCH₂CH₂CH₃, NH(CH₃), NHC(O)O-tert-butyl, morpholino, phenyl or,        more particularly, bromo, pyrazolyl, imidazolyl, benzyl, or,        particularly, chloro, fluoro, CN, ethyl, methyl, isopropyl, CF₃,        CHF₂, CH₂CF₃. CF₂CF₃, OH, OCH(CH₃)₂, OCH₃, OCH₂CH₃, OCH₂F,        OCHF₂, OCH₂CH₃, OCH₂CF₃, OCH₃, OCF₃, (CH₂)₃OH, CH₂OH, CH₂OCH₃,        N(CH₃)₂, cyclopropyl, dioxolanyl, SCH₃, SCH₃. C(O)CH₃,        C(O)CH₂CH₃, C(O)NH₂, C(O)NHCH₃, C(O)N(CH₃)₂, C(O)NHCH₂CH₃,        S(O)CH₃, S(O)₂CH₃, S(O)₂CH₂CH₃, NHC(O)CH₃, NHS(O)₂CH₃, ═O, or        when two R^(4a) or R^(4b) groups are attached to the same carbon        atom in a non-aromatic portion of a Cy¹ or Het^(A) group, they        may form dioxolanyl, which ring optionally contains one to two        heteroatoms selected from O and N, and which ring is optionally        substituted by one or more R^(a) substituents;-   (4) R^(4c) or R^(4d) represent, independently at each occurrence,    -   halo    -   CN,    -   C₁₋₃ alkyl, (which latter group is optionally substituted by one        or more substituents selected from halo and OR^(5a)),    -   OR⁸,    -   N(R^(9f))(R^(9g)) or    -   B⁷—C(G¹)-B⁸—R^(9h)    -   (e.g. R^(4c) or R^(4d) represents, independently at each        occurrence, CH₂OCH₃, or particularly, bromo imidazolyl,        S(O)₂CH₃, ═O or more particularly, chloro, fluoro, CN, methyl,        ethyl, n-propyl, isopropyl, CF₃, CHF₂, CH₂CF₃, OH, OCH, OCH₂F,        OCHF₂, OCH₂CH₃, OCH₂CF₃, OCH₃, OCF₃, N(CH₃)₂, CH₂OH, CH₂OCH₃,        CH₂CN, C(O)CH₃, C(O)CH₂CH₃, NHC(O)CH₃).

In certain embodiments of the invention, the compound of formula Ixb,Iyb or Izb may be represented as a compound of formula Ixb1, Iyb1 orIzb1,

respectively, wherein u1, u2 and u3 independently represent 0 to 4 (e.g.0 to 3 or, particularly 1 or 2) and L¹, R^(4a), R^(4b), R^(4c), R³ t1,t2 and t3 are as defined above in relation to compounds of formula I (orA1 or, particularly, Ix, Iy, Iz, Ia, Ixa, Iya, Iza, Ib, Ixb, Iyb or Izb)(e.g. L¹ represents a bond and R^(4a), R^(4b), R^(4c) and R⁶ are asdefined above in relation to compounds of formula I (or A1 or,particularly, Ix, Iy, Iz, Ia, Ixa, Iya, Iza, Ib, Ixb, Iyb or Izb)).

In certain further embodiments of the invention, the compound of formulaIb, Ixb, Iyb, Izb, Ixb1, Iyb1 or Izb1 (e.g. the compound of Iyb1) is acompound in which:

-   (1) t, t1, t2 or t3 represents 3 or, particularly, 2, 1 or 0; and-   (2) the phenyl group that is substituted by (R^(4c))_(t),    (R^(4c))_(t1), (R^(4c))_(t2) or (R^(4c))_(t3) is unsubstituted in    the ortho-positions relative to the point of attachment to the    1,2,4-triazine group.

In certain other embodiments of the invention, B representsunsubstituted phenyl and L² represents a direct bond and the compound offormula I may be represented as a compound of formula Ic,

wherein A and L¹ are as defined above in relation to compounds offormula I (or A1 or, particularly, la or Ib).

Embodiments of the invention that may be mentioned include those inwhich the compounds of formula I (or A1 or, particularly, Ix, Iy Iz,Ixa, Iya, Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, or, more particularly,Ia, Ib or Ic) are those in which:

-   (1) L¹ represents a bond or O (e.g. L¹ represents a direct bond):-   (2) A represents furanyl, imidazolyl, ketopiperidinyl (e.g.    2-ketopiperidinyl, 3-ketopiperidinyl or 4-ketopiperidinyl),    pyrazinyl, pyrrolidinyl, pyrrolidinonyl, particularly, cyclohexenyl,    pyridinonyl (such as 1-1H-pyridin-2-onyl, 3-1H-pyridin-2-onyl,    4-1H-pyridin-2-onyl, 6-1H-pyridin-2-onyl, or, particularly,    4-pyridinonyl), or more particularly morpholinyl, piperidinyl,    phenyl or pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl),    which A group is optionally substituted by one or more R^(4a) or    R^(4b) substituents, as appropriate;-   (3) R^(4a) or R^(4b) represents, independently at each occurrence,    CH₂F, cyclopropyl, N(Me)₂, Br, ═O, azetidine, or, particularly,    chloro, fluoro, ethyl, methyl, CF₃, CHF₂, CH₂CF₃, CF₂CF₃, OH,    OCH(CH₃)₂, OCH₃, OCH₂CH₃, OCH₂F, OCHF₂, OCH₂CH₃, OCH₂CF₃, OCH₃,    OCF₃, (CH₂)₃OH, CH₂OH or CH₂OCH₃ (e.g. R^(4a) or R^(4b) represents,    independently at each occurrence, chloro, fluoro, ethyl, methyl,    CF₃, CHF₂, CH₂CF₃, CF₂CF₃).

Further embodiments of the invention that may be mentioned relate tocompounds of formula I (or A1 or, particularly, Ia, Ib or, moreparticularly, Ic) in which:

-   (1) L¹ represents a direct bond;-   (2) A represents a non-aromatic, 6-membered Het^(A) ring containing    at least one N atom, which Het^(A) group is optionally substituted    by one or more R^(4b) substituents, wherein the Het^(A) ring is    attached to the remainder of the molecule by the essential N atom.

These embodiments include those in which L¹ represents a direct bond, Arepresents piperidinyl or morpholinyl optionally substituted by one ormore R^(4b) substituents, R¹ represents H, L² represents a direct bondand B represents phenyl optionally substituted by one or more R^(4c)substituents).

Still further embodiments of the invention that may be mentioned relateto compounds of formula I (or A1 or, particularly, Ia, Ib or, moreparticularly, Ic) in which:

-   (1) L¹ represents O;-   (2) A represents a 6-membered Cy¹ group which is optionally    substituted by one or more R^(4a) substituents.

These embodiments include those in which L¹ represents O, A representspyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl or, particularly, phenyloptionally substituted by one or more R^(4a) substituents, R¹ representsH, L² represents a direct bond and B represents phenyl optionallysubstituted by one or more R^(4c) substituents.

In certain other embodiments of the invention, B represents phenyl andL¹ and L² represent a direct bond and the compound of formula I may berepresented as a compound of formula Iyc,

wherein v1 represents 0 to 4 (e.g. 0 to 3 or, particularly 1 or 2), w1independently represents 0 to 5 (e.g. 0 to 3 or, particularly, 0 to 2),and R^(4b) and R^(4c) are as defined above in relation to compounds offormula I (or A1 or, particularly, Iy, Ia, Iya, Ib, Iyb, Iyb1 or Ic).

Embodiments of the invention that may be mentioned relate to compoundsof formula Iyc in which:

-   (1) R^(4b) represents, independently at each occurrence, NMe₂, Br,    azetidin-1-yl, CH₂F or, particularly, chloro, fluoro, ethyl, methyl,    cyclopropyl, CF₃, CHF₂, CH₂CF₃, CF₂CF; or OCH₃;-   (2) R^(4c) represents, independently at each occurrence, CN, chloro,    fluoro, ethyl, methyl, CH₂OCH₃, CF₃, CHF_(2z) CH₂CF₃, CF₂CF₃, OH,    OCH(CH₃)₂, OCH₃, OCH₂CH₃. OCH₂F, OCHF₂, OCH₂CH₃. OCH₂CF₃, OCH₃,    OCF₃, (CH₂)₃OH, CH₂OH or CH₂OCH₃;-   (3) v1 represents 0 to 4;-   (4) w1 represents 0 to 3.

Further embodiments of the invention that may be mentioned relate tocompounds of formula Iyc in which:

-   (1) R^(4b) represents, independently at each occurrence, NMe₂, Br,    azetidin-1-yl, CH₂F, CHF₂ or, particularly, cyclopropyl, OCH₃ or,    more particularly, chloro, methyl or CF₃;-   (2) R^(4c) represents, independently at each occurrence, CN, chloro,    fluoro, CH₂OCH₃, OCH₃, OCH₂CH₃. OCH₂F or OCHF₂;-   (3) v1 represents 1 or 2;-   (4) w1 represents 0 to 3 (e.g. 3 or, particularly, 2, 1 or 0);-   (5) the R^(4b) substituent(s) is (are) attached to the 3- and/or    5-position(s) of the pyridyl group, relative to the point of    attachment to the 1,2,4-triazine group;-   (6) the phenyl ring is either unsubstituted or is substituted by one    to three R^(4c) substituents attached in the meta- and/or    para-positions relative to the point of attachment to the    1,2,4-triazine group.

Still further embodiments of the invention that may be mentioned relateto compounds of formula Iyc in which:

-   (1) R^(4b) represents, independently at each occurrence, NMe₂, Br,    azetidin-1-yl, CH₂F, CHF₂ or, particularly, cyclopropyl, OCH₃ or,    more particularly, chloro, methyl or CF₃;-   (2) R^(4c) represents, independently at each occurrence, CN, chloro,    fluoro, CH₂OCH₃, OCH₃, OCH₂CH₃. OCH₂F or OCHF₂;-   (3) vi represents 1 or 2;-   (4) w1 represents 0 to 3 (e.g. 3 or, particularly, 2, 1 or 0);-   (5) the R^(4b) substituent(s) is (are) attached to the 3- and/or    5-position(s) of the pyridyl group, relative to the point of    attachment to the 1,2,4-triazine group; and-   (6) the phenyl ring is either unsubstituted or is substituted by one    to three R^(4c) substituents attached in the mete- and/or    para-positions relative to the point of attachment to the    1,2,4-triazine group.

Yet further embodiments of the invention that may be mentioned relate tocompounds of formula Iyc in which:

-   (1) v1 represents 1 and the R^(4b) substituent is attached to the    3-position of the pyridyl group, relative to the point of attachment    to the 1,2,4-triazine group;-   (2) v1 represents 2 and the R^(4b) substituents are attached to the    3- and 5-positions of the pyridyl group, relative to the point of    attachment to the 1,2,4-triazine group.

Compounds of formula I (or Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb,Ixb1, Iyb1, Izb1 and Iyc or, more particularly, la, Ib or Ic) that maybe mentioned include those wherein, when A′, A″, A′″ or, particularly, Ais a substituted 6-membered Cy¹ or Het^(A) group (or Cy¹, Het^(A′),Het^(A″) or Het^(A′″) group), the substituent(s) is (are) in the ortho-or, particularly, mete- or para-position(s), relative to the point ofattachment to the rest of the molecule (e.g. when A represents asubstituted 6-membered Cy¹ or Het^(A) group then there is at least onesubstituent in the mete- or para-positions and, optionally, asubstituent in the ortho-position of A or, more particularly, there isat least one substituent in the mete- or para-position and nosubstituents in the ortho-position of A relative to the point ofattachment to the rest of the molecule). In particular embodiments, the6-membered Cy¹, Cy^(1′), Het^(A), Het^(A′), Het^(A″) or Het^(A′″) grouphas:

-   -   no substituents in the ortho-positions;    -   a substituent in one or both of the mete-positions; and,        optionally, for Cy¹, Cy^(1′) or Het^(A)    -   a substituent in the para-position.

For example, in a particular embodiment of the invention, the compoundof formula I (or A1 or, particularly, Ix, Iy Iz, Ia, Ixa, Iya, Iza, Ib,Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Ic or Iyc) may be represented as acompound of formula Ixd, Iyd or Izd,

respectively, wherein:rr1 represents 0 to 3 (e.g. 1 or, particularly 0);rr2 and rr3 independently represent 0 to 2 (e.g. 1 or, particularly 0);ss and tt independently represent, at each occurrence 0 or 1, providedthat ss and tt do not both represent 0;R^(4a′) takes the same definition as R^(4a);R^(4b′) takes the same definition as R^(4b); andB, L¹, L², R^(4a) and R^(4b) are as defined above in relation tocompounds of formula I (or A1 or, particularly, Ix, Iy Iz, Ia, Ixa, Iya,Iza, Ib, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Ic or Iyc).

Embodiments of the invention that may be mentioned relate to compoundsof formulae Ixd, Iyd and Izd in which R^(4a), R^(4a′), R^(4b) andR^(4b′) independently represent cyclopropyl, iodo, bromo, chloro,fluoro, ethyl, methyl, d₃-methyl, iso-propyl, —C≡CH, phenyl, CF₃, CHF₂,CH₂F, CH₂CF₃, CF₂CF₃, CN, ═O, OH, OCH(CH₃)₂, OCH₃, OCH₂CH₃, OCH₂F,OCHF₂, OCH₂CF₃, OCF₃, (CH₂)₃OH, CH₂OH or CH₂OCH₃, CH(CH₃)OH, C(CH₃)₃OH,CH₂CH₂OH, NH₂, N(CH₃)₂, N(H)CH₂CH₃, N(H)C(O)CH₃, C(O)CH₃, C(O)N(CH₃)₂,S(O)₂CH₃, S(O)CH₃, SCH₃, S(O)₂CF₃, azetidine, morpholine or dioxolane(e.g. OH, chloro, fluoro, bromo, ethyl, methyl, d₃-methyl, CF₃, CHF₂,CH₂F, CH₂CF₃, CF₂CF₃, or N(H)C(O)CH₃).

Embodiments of the invention that may be mentioned relate to compoundsof formulae Ixd, Iyd and Izd in which R^(4a), R^(4a′), R^(4b) andR^(4b′) represent, independently at each occurrence

-   (a) halo,-   (b) CN,-   (c) C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, which latter three    groups are optionally substituted by one or more substituents    selected from halo, nitro, CN, OR^(5a), S(O)_(q)R^(5b),    S(O)₂N(R^(5c))(R^(5d)), N(R^(5e))S(O)₂R^(5f), N(R^(5g))(R^(5h)),    B¹—C(G¹)-B²—R^(5i) and Het¹ (e.g. one or more substituents selected    from nitro, CN, OR^(5a), S(O)_(q)R^(5b), S(O)₂N(R^(5c))(R^(5d)),    N(R^(5e))S(O)₂R^(5f), N(R^(5g))(R^(5h)), B¹—C(G¹)-B²—R^(5i) and    Het¹),-   (d) Cy³, which Cy³ group is optionally substituted by one or more    substituents selected from nitro, CN, OR^(6a), S(O)_(q)R^(6b),    S(O)₂N(R^(6c))(R^(6d)), N(R^(6e))S(O)₂R^(6f), N(R^(6g))(R^(6h)),    B³—C(G¹)-B⁴—R^(6i) and Het²,-   (e) Het^(a), which Het^(a) group is optionally substituted by one or    more substituents selected from halo, nitro, CN, OR^(7a),    S(O)_(q)R^(7b), S(O)₂N(R^(7c))(R^(7d)), N(R^(7e))S(O)₂R^(7f),    N(R^(7g))(R^(7h)), B⁵—C(G¹)-B⁶—R^(7i) and Het³,-   (f) OR⁸,-   (g) S(O)_(r)R^(9a),-   (h) S(O)₂N(R^(9b))(R^(9c)),-   (i) N(R^(9d))S(O)₂R^(9e),-   (j) N(R^(9f))(R^(9g)) or-   (k) B⁷—C(G¹)-B⁸—R^(9h),

wherein R^(5a) to R^(5i), R^(6a) to R^(6i), R^(7a) to R^(7i), R⁸, R^(9a)to R^(9h), Cy³, Het¹ to Het³, Het^(a), B¹ to B⁸, G¹, q and r are asdefined above.

Embodiments of the invention that may be mentioned relate to compoundsof formulae Ixd, Iyd and Izd in which:

-   (1) R^(4a) and R^(4b) represent, independently at each occurrence,    OH, OCH(CH₃)₂, OCH₃, OCH₂CH₃, OCH₂F, OCHF₂, OCH₂CH₃, OCH₂CF₃, OCH₃,    OCF₃, (CH₂)₃OH, CH₂OH or CH₂OCH₃, NH₂, NHCH(CH₃), NHCH₃, NHCH₂CH₃,    NHCH₂CH₃, NH(CH(CH₃)₂)₂, NH(CH₃)₂, NH(CH₂CH₃)₂ or NH(CH₂CH₃)₂);-   (2) the sum of ss and tt is 1;-   (3) rr1, rr2 and rr3 are 0;-   (4) L¹ and L² both represent direct bonds.

Further embodiments of the invention that may be mentioned relate tocompounds of formulae Ixd, Iyd and Izd in which:

-   (1) R^(4a) and R^(4b) represent, independently at each occurrence,    CH₂F or, particularly, cyclopropyl, chloro, fluoro, ethyl, methyl,    CF₃, CHF₂, CH₂CF₃. CF₂CF₃, OH, OCH(CH₃)₂, OCH₃, OCH₂CH₃, OCH₂F,    OCHF₂, OCH₂CH₃, OCH₂CF₃, OCH₃, OCF₃, (CH₂)₃OH, CH₂OH or CH₂OCH₃;-   (2) ss and tt are both 1;-   (3) rr1 is 1 or, particularly, 0;-   (4) rr2 and rr3 are 0;-   (5) if present, R^(4a′) is attached at the 4-position relative to L¹    and represents cyclopropyl, chloro, fluoro, ethyl, methyl, CF₃,    CHF₂, CH₂CF₃, CF₂CF₃, OH, OCH(CH₃)₂, OCH₃, OCH₂CH₃, OCH₂F, OCHF₂,    OCH₂CH₃, OCH₂CF₃, OCH₃, OCF₃, (CH₂)₃OH, CH₂OH or CH₂OCH₃;-   (6) L¹ and L² both represent direct bonds.

Still further embodiments of the invention that may be mentioned relateto compounds of formulae Ixd, Iyd and Izd in which:

-   (1) R^(4a) and R^(4b) represent, independently at each occurrence,    CH₂F or, particularly, cyclopropyl, chloro, fluoro, ethyl, methyl,    CF₃, CHF₂, CH₂CF₃, CF₂CF₃, OH, OCH(CH₃)₂, OCH₃, OCH₂CH₃, OCH₂F,    OCHF₂, OCH₂CH₃, OCH₂CF₃, OCH₃, OCF₃, (CH₂)₃OH, CH₂OH or CH₂OCH₃    (e.g. chloro, fluoro, ethyl, methyl, CF₃, CHF₂, CH₂CF₃, CF₂CF₃);-   (2) ss and tt are both 1;-   (3) rr1, rr2 and rr3 are 0; and-   (4) L¹ and L² both represent direct bonds.

Embodiments of the invention that may be mentioned relate to compoundsof formulae Ixd, Iyd and Izd in which R^(4a), R^(4a′), R^(4b) andR^(4b′) are as hereinbefore defined and the compounds are compounds offormula A1 (i.e. wherein L¹ and L² both represent direct bonds; and Brepresents Cy^(BB) or Het^(BB) as hereinbefore defined. In suchembodiments of the invention, R^(4a), R^(4a′), R^(4b) and R^(4b′)independently represent cyclopropyl, iodo, bromo, chloro, fluoro, ethyl,methyl, d₃-methyl, iso-propyl, —C≡CH, phenyl, CF₃, CHF₂, CH₂F, CH₂CF₃,CF₂CF₃, CN, ═O, OH, OCH(CH₃)₂, OCH₃, OCH₂CH₃, OCH₂F, OCHF₂, OCH₂CF₃,OCF₃, (CH₂)₃OH, CH₂OH or CH₂OCH₃, CH(CH₃)OH, C(CH₃)₂OH, CH₂CH₂OH, NH₂,N(CH₃)₂, N(H)CH₂CH₃, N(H)C(O)CH₃, C(O)CH₃, C(O)N(CH₃)₂, S(O)₂CH₃,S(O)CH₃, SCH₃, S(O)₂CF₃, azetidine, morpholine or dioxolane (e.g. OH,chloro, fluoro, bromo, ethyl, methyl, d₃-methyl, CF₃, CHF₂, CH₂F,CH₂CF₃, CF₂CF₃ or N(H)C(O)CH₃).

Other compounds of formula I that may be mentioned include the compoundsof the examples described hereinafter. Thus, embodiments of theinvention that may be mentioned include those in which the compound offormula I is a compound selected from the list:

-   (i) 5,6-diphenyl-1,2,4-triazin-3-amine; or, particularly,-   (ii) 6-(2-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (iii) 6-(3-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (iv) 6-(4-fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (v) 6-(5-chloro-2-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (vi) 6-(3-chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (vii) 6-(4-chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (viii) 5-phenyl-6-(piperidin-1-yl)-1,2,4-triazin-3-amine;-   (ix) 6-(2-chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (x) 6-(furan-2-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (xi) 6-phenoxy-5-phenyl-1,2,4-triazin-3-amine;-   (xii) 6-(morpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (xiii) 6-(3-methylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (xiv) 6-(4,4-difluoropiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (xv) 6-(3-fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine;-   (xvi) 6-(4-fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine;-   (xvii) 6-(2-fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine;-   (xviii) 6-(4-methoxyphenoxy)-5-phenyl-1,2,4-triazin-3-amine;-   (xix)    6-(3-chlorophenyl)-5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine;-   (xx) 5-phenyl-6-(3,4,5-trifluorophenyl)-1,2,4-triazin-3-amine;-   (xxi) 6-2,6-dimethylmorpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (xxii)    5-phenyl-6-[3-(trifluoromnethyl)phenoxy]-1,2,4-triazin-3-amine;-   (xxiii) 6-(3-chlorophenyl)-5-(3-methoxyphenyl-1,2,4-tiazin-3-amine;-   (xxiv) 5-phenyl-6-[3-(trifluoromethyl)phen]-1,2,4-triazin-3-amine;-   (xxv) 6-(3,5-difluorophenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (xxvi) 5-phenyl-6-[2-(propan-2-yl)phenoxy-1,2,4-triazin-3-amine;-   (xxvii)    6-(3-fluoro-5-(trifluoromiethyl)phenyl]-5-phenyl-1,2,4-triazin-3-amine;-   (xxviii) 6-(3,5-dichlorophenyl)-5-phenyl-1,2,4-triazin-3-amine:-   (xxix) 6-(5-chloropyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (xxx) 6-(3-chloro-4-fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (xxxi) 6-(3-fluoro-5-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (xxxii)    6-[4-fluoro-3-(trifluoromethyl)phenoxy]-5-phenyl-1,2,4-triazin-3-amine;-   (xxxiii)    5-phenyl-6-[3-(trifluoromethoxy)phenoxy]-1,2,4-triazin-3-amine;-   (xxxiv) 6-(3-chlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;-   (xxxv) 6-(3-chloro-5-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (xxxvi) 6-(3-aminophenoxy)-5-phenyl-1,2,4-triazin-3-amine:-   (xxxvii) 6-(3-chlorophenoxy)-5-phenyl-1,2,4-triazin-3-amine;-   (xxxviii)    6-(3,3-dimethylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (xxxix) 6-(3-bromophenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (xl) 6-(3,5-dichlorophenoxy)-5-phenyl-1,2,4-triazin-3-amine;-   (xli)    5-phenyl-6-[3-(trifluoromethyl)piperidin-1-yl]-1,2,4-triazin-3-amine;-   (xlii) 6-(1H-indol-6-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (xliii) 6-(3,5-difluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine;-   (xliv) 6-(octahydroquinolin-1    (2H)-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (xlv) 6-(3,4-dichlorophenyl)-5-phenyl-1,2,4-triazin-3-amine:-   (xlvi) 6-(3-fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (xlvii) 6-(1,3-benzodioxol-5-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (xlvii) 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)benzonitrile;-   (xlix) 6-(3,5-dimethoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (l) 6-(3,5-dimethylphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (li) 6-(3,4-dimethylphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lii) 6-[3-(dimethylamino)phenyl]-5-phenyl-1,2,4-triazin-3-amine;-   (liii) N-[3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]acetamide;-   (liv)    N-[3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]methanesulfonamide;-   (lv) 6-(3-trifluoromethoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lvi) 6-(1-benzofuran-5-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (lvii) 5-phenyl-6-[3-(propan-2-yl)phenyl]-1,2,4-triazin-3-amine;-   (lviii)    6-(3,5-dichlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;-   (lix)    6-(3,5-bis(trifluormethyl)phenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lx) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenol;-   (lxi) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2,6-dimethylphenol-   (lxii) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-chlorophenol;-   (lxiii) 6-(2-chloropyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxiv) 6-(3-(methylsulfonyl)phenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxv)    6-(3,5-dichloro-4-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxvi)    6-(4-methoxy-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxvii)    6-(3-chloro-5-(dimethylamino)phenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxviii)    3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)benzonitrile;-   (lxix)    4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;-   (lxx)    6-(3-chloro-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxxi) 6-(3-chloro-5-methylphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxxii)    6-(3-(methylthio)-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxxiii)    6-(3-methoxy-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxxiv)    6-(3-ethoxy-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxxv)    6-(3-tert-butyl-5-methylphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxxvi)    6-(2-chloro-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxxvii)    4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-chlorobenzonitrile;-   (lxxviii) 6-(3-ethylphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxxix)    6-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxxx)    6-(3-methyl-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxxxi)    6-(3-(1,3-dioxolan-2-yl)-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxxxii)    5-phenyl-6-(3-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-triazin-3-amine;-   (lxxxiii)    6-(3-(methoxymethyl)phenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxxxiv)    5-(3-amino-5-phenyl-1,2,4-triazin-1-yl)-1-methylpyridin-2(1H)-one;-   (lxxxv)    6-3-methyl-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxxxvi) 6-(2-methoxypyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (lxxxvii) 1-(3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)phenyl)ethanone;-   (lxxxviii) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)benzamide;-   (lxxxix)    6-(4-fluoro-3-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (xc) 6-(4-fluoromethylphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (xci) 6-(3-bromo-5-chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine:-   (xcii) 6-naphthalen-2-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (xciii) 5-phenyl-6-m-tolyl-1,2,4-triazin-3-amine;-   (xciv) 5-phenyl-6-(pyridin-4-yl)-1,2,4-triazin-3-amine;-   (xcv) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)phenol;-   (xcvi) 6-(2,6-dimethoxypyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (xcvii) 6-(2,6-dimethylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine:-   (xcviii)    5-phenyl-6-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-triazin-3-amine;-   (xcix) 6-(2-cyclopropylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (c)    5-phenyl-6-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)-1,2,4-triazin-3-amine;-   (ci)    6-(5-chloro-2-fluoro-3-methylphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (cii) 6-(2,6-dichloropyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (ciii)    6-(3-bromo-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazin-3-amine:-   (civ)    4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-chloro-6-methoxyphenol;-   (cv) 6-(3,5-dichloro-4-ethoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (cvi)    6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (cvii)    4-(3-amino-5-(3-fluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;-   (cviii)    6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3-fluorophenyl)-1,2,4-triazin-3-amine;-   (cix)    6-(2-chloro-6-methylpyridin-4-yl)-5-(3-fluorophenyl)-1,2,4-triazin-3-amine;-   (cx)    4-(3-amino-5-(4-fluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;-   (cxi) 6-(3-chloro-5-propoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (cxii)    6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;-   (cxiii)    6-(2-chloropyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;-   (cxiv)    6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;-   (cxv)    4-(3-amino-5-(4-chlorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;-   (cxvi)    6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-chlorophenyl)-1,2,4-triazin-3-amine;-   (cxvii)    5-(4-chlorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazin-3-amine;-   (cxviii)    6-(2-chloro-6-methylpyridin-4-yl)-5-(4-chlorophenyl)-1,2,4-triazin-3-amine;-   (cxix)    4-(3-amino-5-(3-chlorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitriile;-   (cxx)    6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3-chlorophenyl-1,2,4-triazin-3-amine;-   (cxxi)    5-(3-chlorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazin-3-amine;-   (cxxii)    6-(2-chloro-6-methylpyridin-4-yl)-5-(3-chlorophenyl)-1,2,4-triazin-3-amine;-   (cxxiii)    4-(3-amino-6-(3-chloro-5-(trifluoromethyl)phenyl)-1,2,4-triazin-5-yl)benzonitrile;-   (cxxiv)    4-(3-amino-6-(2-chloro-6-methylpyridin-4-yl)-1,2,4-triazin-5-yl)benzonitrile;-   (cxxv)    4-(3-amino-5-(3-chloro-5-fluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;-   (cxxvi)    5-(3-chloro-5-fluorophenyl)-6-(2-chloro-6-methylpyridin-4-yl)-1,2,4-triazin-3-amine;-   (cxxvii)    6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazin-3-amine;-   (cxxviii)    6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3,5-difluorophenyl)-1,2,4-triazin-3-amine;-   (cxxix)    6-(2-chloro-6-methylpyridin-4-yl)-5-(3,5-difluorophenyl)-1,2,4-triazin-3-amine;-   (cxxx)    4-(3-amino-5-(3,5-difluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;-   (cxxxi)    4-(3-amino-5-(3-chloro-4-fluorphenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;-   (cxxxii)    5-(3-chloro-4-fluorophenyl)-6-(2-chloro-6-methylpyridin-4-yl-1,2,4-triazin-3-amine;-   (cxxxiii)    5-(3-chloro-4-fluorophenyl)-6-(2-chloropyridin-4-yl-1,2,4-triazin-3-amine;-   (cxxxiv)    5-(3-chloro-4-fluorophenyl)-6-(3-chloro-5-(trifluoromethyl)phenyl)-1,2,4-triazin-3-amine;-   (cxxxv)    4-(3-amino-5-(3,4-difluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;-   (cxxxvi)    6-(2-chloro-6-methylpyridin-4-yl)-5-(3,4-difluorophenyl)-1,2,4-triazin-3-amine;-   (cxxxvii)    6-(2-chloropyridin-4-yl)-5-(3,4-difluorophenyl)-1,2,4-triazin-3-amine;-   (cxxxviii)    6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3,4-difluorophenyl)-1,2,4-triazin-3-amine;-   (cxxxix)    6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-(methoxymethyl)phenyl)-1,2,4-triazin-3-amine;-   (cxl)    6-(2-chloro-6-methylpyridin-4-yl)-5-(4-(methoxymethyl)phenyl)-1,2,4-triazin-3-amine;-   (cxli)    6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;-   (cxlii)    6-(3-chloro-5-methylphenyl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;-   (cxliii) 6-(6-fluoropyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (cxliv)    6-(3,5-dimethylisoxazol-4-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (cxlv) 6-(3,5-diisopropylphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (cxlvi)    6-3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (cxlvii)    N-(4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-(trifluoromethyl)phenyl)acetamide;-   (cxlviii)    5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-fluorobenzonitrile;-   (cxlix)    3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-N,N-dimethylbenzamide;-   (cl) 6-1-methy-1H-pyrazol-4-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (cli)    4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-1-methylpyridin-2(1H)-one;-   (clii) 6-(3-(morpholin-4-yl)phenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (cliii) 6-(1-benzyl-1H-pyrazol-4-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (cliv) 6-(2-methoxypyrimidin-5-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (clv) 6-(6-methoxypyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (clvi) 6-(3-(methylsulfinyl)phenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (clvii)    4-(3-amino-6-(2-chloropyridin-4-yl)-1,2,4-triazin-5-yl)benzonitrile;-   (clviii)    4-(3-amino-5-(4-(methoxymethyl)phenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile; (clix)    6-(2-chloropyridin-4-yl)-5-(4-(methoxymethyl)phenyl)-1,2,4-triazin-3-amine;-   (clx) 6(E)-5-phenyl-6-styryl-1,2,4-triazin-3-amine;-   (clxi) 6-(3-amino-5-phenyl-1,2,4-triazin-6-yl)indolin-2-one;-   (clxii) tert-butyl    5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)pyridin-2-yl(methyl)carbamate;-   (clxiii) 6-(3-methoxypiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (clxiv) 6-(3-ethynylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (clxv)    6-2,6-dimethylmorpholin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;-   (clxvi) 6-(2-ethylmorpholino)-5-phenyl-1,2,4-tiazin-3-amine;-   (clxvii)    5-phenyl-6-(6-oxa-9-azaspiro[4.5]decan-9-yl)-1,2,4-triazin-3-amine;-   (clxviii) 6-(2,2-diethylmorpholino)-5-phenyl-1,2,4-triazin-3-amine;-   (clxix) 6-(2,2-dimethylmorpholino)-5-phenyl-1,2,4-triazin-3-amine;-   (clxx)    (1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3-methylpiperidin-3-yl)methanol;-   (clxxi)    6-(3-(methoxymethyl)piperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (clxxii)    1-(1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)piperidin-3-yl)ethanal;-   (cdxxiii)    (1-(3-amino-5-phenyl-1,2,4-tiazin-6-yl)piperidin-3-yl)methanol;-   (clxxiv)    1-(1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)piperidin-3-yl)ethanone;-   (clxxv)    6-(octahydroisoquinolin-2(1H)-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (clxxvi)    N6-(4-methyl-1,3-thiazol-2-yl)-5-phenyl-1,2,4-triazine-3,6-diamine;-   (clxxvii)    5-phenyl-6-[4-(trifluoromethyl)piperidin-1-yl]-1,2,4-triazin-3-amine;-   (clxxviii)    5-phenyl-6-(3-phenylpiperidin-1-yl)-1,2,4-triazin-3-amine;-   (clxxix)    (4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)morpholin-2-yl)methanol;-   (clxxx)    5-phenyl-6-(3-(propoxymethyl)pyrrolidin-1-yl)-1,2,4-triazin-3-amine;-   (clxxxi)    2-(1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)piperidin-3-yl)propan-2-ol;-   (clxxxii)    6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (clxxxiii)    1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3-ethylpiperidin-3-ol;-   (clxxxiv)    2-(4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)morpholin-2-yl)ethanol;-   (clxxxv) 6-(3,5-dimethylphenoxy)-5-phenyl-1,2,4-triazin-3-amine;-   (clxxxvi)    6-(3-chloro-5-methoxyphenoxy)-5-phenyl-1,2,4-triazin-3-amine;-   (clxxxvii) 1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)pyridin-4(1H)-one;-   (clxxxviii) 6-(4-methylphenoxy)-5-phenyl-1,2,4-triazin-3-amine;-   (clxxxix) 6-(4-chlorophenoxy)-5-phenyl-1,2,4-triazin-3-amine;-   (cxc) 6-(3,4-difluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine;-   (cxci)    6-[(6-methoxypyridin-3-yl)oxy]-5-phenyl-1,2,4-triazin-3-amine;-   (cxcii)    6-[(2-methylpyridin-3-yl)oxy]-5-phenyl-1,2,4-triazin-3-amine;-   (cxciii)    6-[(6-chloropyridin-3-yl)oxy]-5-phenyl-1,2,4-triazin-3-amine;-   (cxciv) 4-[(3-amino-5-phenyl-1,2,4-triazin-6-yl)oxy]benzonitrile;-   (cxcv)    6-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy}-5-phenyl-1,2,4-triazin-3-amine;-   (cxcvi)    6-[(1-methyl-1H-benzimidazol-5-yl)oxy]-5-phenyl-1,2,4-triazin-3-amine;-   (cxcvii) 1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)pyridazin-4(1H)-one;-   (cxcviii)    1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3,5-dichloropyridin-4(1H)-one;-   (cxcix) 6-(2,4-difluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine;-   (cc) 5-phenyl-6-(pyridin-3-yloxy)-1,2,4-triazin-3-amine;-   (cci) 6-[(4-methylpyridin-3-yl)oxy]-5-phenyl-1,2,4-triazin-3-amine;-   (ccii) 5-phenyl-6-(p-tolylthio)-1,2,4-triazin-3-amine;-   (cciii) 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenol;-   (cciv) 6-(3-chloro-5-ethenylphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (ccv)    6-(3-chloro-5-cyclopropylphenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (ccvi)    6-(3,5-dichlorophenyl)-5-(3-methylpiperidin-1-yl)-1,2,4-triazin-3-amine;-   (ccvii)    6-(6-(methylamino)pyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (ccviii)    5-(3-chloro-5-fluorophenyl)-8-(2-chloropyridin-4-yl)-1,2,4-triazin-3-amine;-   (ccix)    6-(2-chloropyridin-4-yl)-5-(3,5-difluorophenyl)-1,2,4-triazin-3-amine;-   (ccx)    4-(3-amino-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;-   (ccxi)    6-(2-chloro-6-methylpyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-amine;-   (ccxii)    6-(2-chloropyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-amine;-   (ccxiii)    6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-amine;-   (ccxiv)    5-(3-amino-5-(3-fluorophenyl)-1,2,4-triazin-6-yl)-2-chlorophenol;-   (ccxv)    4-[3-amino-6-(3-chloro-4-hydroxyphenyl)-1,2,4-triazin-5-yl]benzonitrile;-   (ccxvi)    3-(3-amino-5-phenyl-1,2,4-triazin-8-yl)-5-(trifluoromethoxy)phenol;-   (ccxvii)    5-(3-chloro-5-fluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine;-   (ccxviii)    5-3,5-difluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine;-   (ccxix)    5-(3,4-difluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine;-   (ccxx)    5-(3-chloro-4-fluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine;-   (ccxx)    5-(4-(difluoromethoxy)phenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine;-   (ccxxii)    6-(2,6-dimethylpyridin-4-yl)-5-(3-fluorophenyl)-1,2,4-triazin-3-amine;-   (ccxxiii)    5-(4-chlorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine;-   (ccxxiv)    4-(3-amino-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-5-yl)benzonitrile;-   (ccxxv)    5-(3-chlorophenyl-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine;-   (ccxxvi)    6-(2,6-dimethylpyridin-4-yl)-5-(4-(methoxymethyl)phenyl)-1,2,4-triazin-3-amine;-   (ccxxvii)    4-(3-amino-6-(3-chloro-4-hydroxy-5-methoxyphenyl)-1,2,4-triazin-5-yl)benzonitrile;-   (ccxxviii) 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-chlorophenol;-   (ccxxix) 6-(6-chloropyridin-2-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (ccxxx)    6-(4-cyclopropylpyridin-2-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (ccxxxi)    5-phenyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,2,4-triazin-3-amine;-   (ccxxxii)    5-phenyl-6-(4-(trifluoromethyl)pyridin-2-yl)-1,2,4-triazin-3-amine;-   (ccxxxiii)    6-(6-cyclopropylpyridin-2-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (ccxxxiv) 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)pyrazin-2-o;-   (ccxxxv) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2,6-diiodophenol;-   (ccxxxvi) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-iodophenol;-   (ccxxxvii)    6-(3-methoxy-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazin-3-amine;-   (ccxxxviii)    4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-(propan-2-yloxy)phenol;-   (ccxxxix)    5-(3-fluorophenyl)-8-(2-chloropyridin-4-yl)-1,2,4-triazin-3-amine;-   (ccxl) 6-(2,4 dichlorophenoxy)-5-phenyl-1,2,4-triazin-3-amine;-   (ccxli)    6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(3,4-difluorophenyl)-1,2,4-triazin-3-amine;-   (ccxlii)    6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(3,5-difluorophenyl)-1,2,4-triazin-3-amine;-   (ccxliii)    6-[2-(ethylamino)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;-   (ccxliv)    6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(3-fluorophenyl-1,2,4-tiazin-3-amine;-   (ccxlv)    6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;-   (ccxlvi)    6-{2-[ethyl(methyl)amino]-6-methylpyridin-4-yl}-5-phenyl-1,2,4-triazin-3-amine;-   (ccxlvii)    6-[2-(dimethylamino)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;-   (ccxlviii)    1-[6-(2,6-d6-dimethylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (ccxlix)    6-[2-d3-methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;-   (ccl)    5-(4-fluorophenyl)-6-[2-d3-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine;-   (ccli)    6-(2,6-dimethylpyridin-4-yl)-5-(2-fluorophenyl)-1,2,4-triazin-3-amine;-   (cclii)    6-(2-chloro-6-methylpyridin-4-yl)-5-(2-fluorophenyl)-1,2,4-triazin-3-amine;-   (ccliii)    6-(2,6-dimethylpyridin-4-yl)-5-(4-methoxyphenyl)-1,2,4-triazin-3-amine:-   (ccliv)    6-2-chloro-6-methylpyridin-4-yl)-5-(4-methoxyphenyl)-1,2,4-triazin-3-amine;-   (cclv)    6-[2-(difluoromethyl-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;-   (cclvi)    6-[2-chloro-6-(difluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;-   (cclvii)    6-[2-chloro-6-(fluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;-   (cclviii)    6-[2-(difluoromethyl)-6-methylpyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;-   (cclix)    6-[2,6-bis(fluoromethyl)pyridine-4-yl]-5-phenyl-1,2,4-triazin-3-amine;-   (cclx)    6-[2-(fluoromethyl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;-   (cclxi)    6-2-chloro-6-methylpyridin-4-yl)-5-(2,5-difluorophenyl-1,2,4-triazin-3-amine;-   (cclxii)    6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(2-fluorophenyl)-1,2,4-triazin-3-amine;-   (cclxiii)    6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(2,5-difluorophenyl)-1,2,4-triazin-3-amine;-   (cclxiv)    6-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;-   (cclxv)    6-[2-ethyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;-   (cclxvi)    6-(2-cyclopropyl-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (cclxvii)    5-(2-fluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine;-   (cclxviii)    5-(3-fluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine;-   (cclxix)    5-(4-fluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine;-   (cclxx)    5-(2,5-difluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine;-   (cclxxi)    5-(3,4-fluorophenyl-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine;-   (cclxxii)    5-(3,5-fluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine;-   (cclxxiii)    6-[2-(azetidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;-   (cclxxiv)    6-[2-methyl(morpholin-4-yl)pyridin-4-yl-5-phenyl-1,2,4-triazin-3-amine:-   (cclxxv)    6-(2-chloro-6-methylpyridin-4-yl)-5-(4-ethylphenyl)-1,2,4-triazin-3-amine;-   (cclxxvi)    5-(2,5-difluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine;-   (cclxxvii)    6-(2,6-dimethylpyridin-4-yl)-5-(4-methylphenyl)-1,2,4-triazin-3-amine;-   (cclxxviii)    6-[2-(difluoromethyl)-6-methylpyridin-4-yl]-5-(3-fluorophenyl)-1,2,4-triazin-3-amine;-   (cclxxix)    6-2-(difluoromethyl)-6-methylpyridin-4-yl]-5-(2-fluorophenyl)-1,2,4-triazin-3-amine;-   (cclxxx)    6-(3,5-dichlorophenyl)-5-(pyridin-2-yl)-1,2,4-triazin-3-amine;-   (cclxxxi)    6-(3-chloro-5-methylphenyl)-5-(pyridin-2-yl)-1,2,4-triazin-3-amine;-   (cclxxxii)    6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;-   (cclxxxiii)    6-[2,6-bis(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;-   (cclxxxiv)    6-[3-chloro-5-(trifluoromethyl)phenyl]-5-(pyridin-2-yl)-1,2,4-triazin-3-amine;-   (cclxxxv)    6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;-   (cclxxxvi)    6-3,5-dimethylphenyl)-5-(pyridin-2-yl)-1,2,4-triazin-3-amine;-   (cclxxxvii)    6-[2-(dimethylamino)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;-   (cclxxxviii)    6-2-bromo-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (cclxxxix)    6-(2,6-dimethyl-1-oxidopyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (ccxc)    4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-6-methylpyridine-2-carbonitrile;-   (ccxci)    6-(3,5-dichlorophenyl)-5-(pyridin-3-yl)-1,2,4-triazin-3-amine;-   (ccxcii)    6-(3-chloro-5-methylphenyl)-5-(pyridin-3-yl)-1,2,4-triazin-3-amine;-   (ccxciii)    6-(3,5-dichlorophenyl)-5-(pyrimidin-2-yl)-1,2,4-triazin-3-amine;-   (ccxciv)    6-[3-chloro-5-(trifluoromethyl)phenyl]-5-(pyrimidin-2-yl-1,2,4-triazin-3-amine;-   (ccxcv)    6-[2-bromo-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;-   (ccxcvi)    6-[3-chloro-5-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1,2,4-triazin-3-amine;-   (ccxcvii)    6-(3-chloro-5-methylphenyl)-5-(pyrimidin-2-yl)-1,2,4-triazin-3-amine;-   (ccxcviii)    N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide;-   (ccxcix)    N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-hydroxyphenyl]acetamide;-   (ccc)    6-(2-methyl-6-d3-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;-   (ccci)    1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3,5-dimethylpyridin-4(1H)-one;-   (cccii)    6-[2-(azetidin-1-yl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;-   (ccciii)    6-[2-(azetidin-1-yl)-6-methylpyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;    and-   (ccciv)    6-[2-(azetidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine.

Particular compounds that may be mentioned include compounds (iii), (v),(vi), (xiii), (xix) to (xxi), (xxiii) to (xxv), (xxvii) to (xxxi),(xxxiv), (xxxv), (xxxviii), (xxxix), (xli), (xlv), (xlvi), (xlviii) to(lv), (lvii) to (lxxxvii), (lxxxix) to (xci), (xciii), (xcvi) to(cxlii), (cxlv) to (cxlix), (cli), (clii), (clvi) to (clix) to (clxxiv),(clxxviii), (clxxix), (clxxxi), (clxxxiii), (clxxxiv), (clxxxvii),(cxcvii), (cxcviii), (cciii) to (ccv), (ccviii) to (ccxxxiii), (ccxxxv)to (ccxxxix), and (ccxli) to (ccciv) above.

Other particular compounds that may be mentioned include compounds(iii), (v), (vi), (xiii), (xix) to (xxi), (xxiii) to (xxv), (xxvii) to(xxxi), (xxxiv), (xxxv), (xxxviii), (xxxix), (xli), (xiv), (xlvi),(xlviii) to (lv), (lvii) to (lxxxvii), (lxxxix) to (xci), (xciii),(xcvi) to (cxlii), (cxlv) to (cxlix), (cli), (clii), (clvi) to (clix),(clxiii) to (clxxiv), (clxxviii), (clcxxix), (clxxxi), (clxxxiii),(clxxxiv), (clxxxvii), (cxcvii), (cxcviii), (cciii) to (ccv), (ccviii)to (ccxxxiii), (ccxxxv) to (ccxxxix), and (ccxli) to (ccciv) above.

More particular compounds that may be mentioned include compounds(xxviii), (lix), (lxi), (lxiii), (lxxi), (lxxvi), (lxxxv), (lxxxvi),(xci), (xcvii), (xcviii), (xcix), (cii), (cviii), (cix), (cxii), (cxiv),(cxvi), (cxvii), (cxx), (cxxi), (cxxviii), (cxxxiii), (cxli), (cxlii),(clxxxvii), (ccxvi), (ccxviii), (ccxxii), (ccxxiii), (ccxxvii), (ccxxx),(ccxxxvi), (ccxxxviii), (ccxxxix), (ccxlv), (ccxlix), (ccl), (cclii),(cclv), (cclvi), (cclvii), (cclx), (cclxii), (cclxiii), (cclxvi),(cclxvii), (cclxviii), (cclxix), (cclxxii), (cclxxxii), (cclxxxv),(cclxxxviii), (ccxcv), (ccxcix) and (cccii) above.

Still more particular compounds that may be mentioned include compounds(lxi), (cxiv), (ccl), (cclv) to (cclvii), (cclx), (cclxxxv), (cclxxxvii)and (ccxcix) above.

Other compounds that may be mentioned include:

-   -   compounds (ii) to (ccxl) above (e.g. compounds (ii) to (lxvii)        above); and    -   compounds (lxxvi), (cix), (xcvii), (cxiv), (cxli), (ccxvii),        (ccxviii), (ccxxii), (ccxxiii) and (ccxxv) above.

For the avoidance of doubt, references herein to compounds of formula Iinclude, where the context permits, references to any of compounds offormula I, A1, Ia, Ib or Ic, Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb,Ixb1, Iyb1, Izb1, Iyc, Ixd, Iyd or Izd (or, in certain embodiments, tocompounds of formula I, Ia, Ib or Ic). Further, references to any ofcompounds of formula I, A1, Ia, Ib or Ic includes references to suchcompounds per se, to tautomers of such compounds, as well as topharmaceutically acceptable salts or solvates, or pharmaceuticallyfunctional derivatives of such compounds.

Certain compounds described herein may be novel. Thus, a further aspectof the invention relates to a compound of formula I (or A1, Ia, Ib, Ic,Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Iyc, Ixd, Iydor Izd (or, in certain embodiments, of formula I, A1, Ia, Ib or Ic)), ora pharmaceutically acceptable salt or solvate, or a pharmaceuticallyfunctional derivative thereof as described hereinbefore, provided thatthe compound is not:

-   (a) 5,6-Diphenyl-[1,2,4]triazin-3-ylamine;-   (b)    5-(2-chlorophenyl)-6-(3,4-dimethoxyphenyl)-[1,2,4]triazin-3-ylamine;-   (c) 5,6-di-p-tolyl-[1,2,4]triazin-3-ylamine;-   (d) 5-(4-dimethylaminophenyl)-6-phenyl-[1,2,4]triazin-3-ylamine;-   (e)    6-(4-dimethylaminophenyl)-5-(4-methoxyphenyl)-[1,2,4]triazin-3-ylamine;-   (f)    5-(2-chlorophenyl)-6-(3,4,5-trimethoxyphenyl)-[1,2,4]triazin-3-ylamine;-   (g) N*5*-(2,4-dichlorophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;-   (h) N*5′-(4-chlorophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;-   (i) N*5*-(4-bromophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;-   (j) 6-phenyl-N*5′-p-tolyl-[1,2,4]triazine-3,5-diamine;-   (k) N*5′-(4-methoxyphenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;-   (l) 2-[5,6-bis-(4-methoxyphenyl)-[1,2,4]triazin-3-ylamino]-ethanol;-   (m)    1-[5-(4-dimethylaminophenyl)-6-(4-methanesulfinylphenyl)-[1,2,4]triazin-3-ylamino]-butan-2-ol;-   (n)    2-[5-(4-dimethylaminophenyl)-6-(4-methoxyphenyl)-[1,2,4]triazin-3-ylamino]-ethanol;-   (o)    2-[6-(4-fluorophenyl)-5-(4-propoxyphenyl)-[1,2,4]triazin-3-ylamino]-ethanol;-   (p)    1-[5-(4-dimethylaminophenyl)-6-(4-methoxyphenyl)-[1,2,4]triazin-3-ylamino]-butan-2-ol;-   (q)    2-[5-(4-dimethylaminophenyl)-6-(4-methanesulfinylphenyl)-[1,2,4]triazin-3-ylamino]-ethanol;-   (r)    1-[6-(4-ethoxyphenyl)-5-(4-methanesulfinylphenyl)-[1,2,4]triazin-3-ylamino]-butan-2-ol;-   (s)    1-[5,6-bis-(4-methanesulfinylphenyl)-[1,2,4]triazin-3-ylamino]-propan-2-ol;-   (t)    1-[5,6-bis-(4-methanesulfinylphenyl)-[1,2,4]triazin-3-ylamino]-butan-2-ol;-   (u)    2-[5-(4-dimethylaminophenyl-6-(4-fluorophenyl)-[1,2,4]triazin-3-ylamino]-ethanol;-   (v) 6-benzyl-5-piperidin-1-yl-[1,2,4]triazin-3-ylamine;-   (w) 6-benzyl-N*5*-phenyl-[1,2,4]triazine-3,5-diamine;-   (x) 5-benzyl-6-phenyl-[1,2,4]triazin-3-ylamine;-   (y) N*5*-(2,4-dichlorophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;-   (z) 6-phenyl-N*5*-o-tolyl-[1,2,4]triazine-3,5-diamine;-   (aa) N*5*(4-bromophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;-   (bb)    N*5*(3-chloro-4-fluorophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;-   (cc) N*5*-(2-bromophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;-   (dd) N*5*(2-chlorophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;-   (ee) N*5*-(4-iodophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;-   (ff) N*5*-(4-chlorophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;-   (gg) N*5*-(4-fluorophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;-   (hh) N*5*(4-chlorophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;-   (ii) N*5*(4-methoxyphenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;-   (jj) N*5*(4-methylphenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;-   (kk) 6,N*5*-diphenyl-[1,2,4]triazine-3,5-diamine;-   (ll)    (2S,3S,4S,5R,6R)-6-[3-amino-6-(2,3-dichlorophenyl)-[1,2,4]triazin-5-ylamino]-3,4,5-trihydroxytetrahydropyran-2-carboxylic    acid;-   (mm) (5,6-diphenyl-[1,2,4]triazin-3-yl)-methylamine;-   (nn) (5,6-difuran-2-yl-[1,2,4]triazin-3-yl)-methylamine;-   (oo) 5,6-bis-(4-methoxyphenyl)-[1,2,4]triazin-3-ylamine;-   (pp) butyl-(5,6-diphenyl-[1,2,4]triazin-3-yl)-amine;-   (qq)    N*4*-[5,6-bis-(4-chlorophenyl)-[1,2,4]triazin-3-yl]-N*1,N*1*-diethylpentane-1,4-diamine;-   (rr)    N′-[5,6-bis-(4-chlorophenyl)-[1,2,4]triazin-3-yl]-N,N-dibutylpropane-1,3-diamine;-   (ss)    N′-[5,6-bis-(4-chlorophenyl)-[1,2,4]triazin-3-yl]-N,N-diethylpropane-1,3-diamine;-   (tt)    3-[5,6-bis-(4-chlorophenyl)-[1,2,4]triazin-3-ylamino]-propan-1-ol;-   (uu)    N,N-dibutyl-N′-(5,6-diphenyl-[1,2,4]triazin-3-yl)-propane-1,3-diamine;-   (vv)    N′-(5,6-diphenyl-[1,2,4]triazin-3-yl)-N,N-diethylpropane-1,3-diamine;    and-   (ww) 3-(5,6-diphenyl-[1,2,4]triazin-3-ylamino)-propan-1-ol.

In this aspect of the invention the compound may be a compound offormula I (or A1 or, particularly, Ia, Ib, Ic, Ix, Iy Iz, Ixa, Iya, Iza,Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Iyc, Ixd, Iyd or Izd (or, in certainembodiments, of formula I, Ia, Ib or Ic)), or a pharmaceuticallyacceptable salt or solvate, or a pharmaceutically functional derivativethereof as described hereinbefore, provided that the compound is not

-   (a) 2-(5,6-diphenyl-[1,2,4]triazin-3-ylamino)-ethan-1-ol;-   (b) 3-amino-5,6-bis(2-chlorophenyl)-1,2,4-triazine; and-   (c) 3-amino-5,6-bis(furan-2-yl)-1,2,4-triazine.

Similarly, other compounds of formula I may be novel. In this respect,other aspects of the invention relate to compounds of formula I (or Ia,Ib, Ic, Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Iyc,Ixd, Iyd or Izd (or, in certain embodiments, of formula I, Ia, Ib orIc)) as described hereinbefore, wherein,

-   (i) when L¹ represents a bond or CH₂, L² represents a bond, CH₂ or    NH, B represents unsubstituted phenyl and A represents phenyl, then    A is substituted by one or more R^(4a) substituents;-   (ii) when L¹ represents a bond, L² represents a bond or NH, B    represents phenyl monosubstituted by CH₃, OCH₃, N(CH₃)₂ or Cl in the    para-position, Cl in the ortho-position or disubstituted by Cl in    the ortho- and para-position, and A represents phenyl, then A is    substituted by one or more R^(4a) substituents provided that A is    not monosubstituted by CH₃, OCH₃, N(CH₃)₂ or Cl in the    para-position;-   (iii) when L¹ represents a bond, L² represents a bond, R¹ represents    —CH₂CH₂OH, —CH₂CH(OH)CH₃ or —CH₂CH(OH)CH₂CH₃, A represents phenyl    substituted in the para-position with OR⁷, N(CH₃)₂, F or S(O)CH₃ and    B represents phenyl, then B is not substituted in the pare position    of the phenyl ring by OR⁷, N(CH₃)₂, F or S(O)CH₃;-   (iv) when L¹ represents CH₂, L² represents a bond, B represents    unsubstituted piperidinyl linked to the rest of the molecule via the    nitrogen atom of the piperidinyl group and A represents phenyl, then    A is substituted by one or more R^(4a) substituents;-   (v) when L¹ represents a bond, L² represents NH, B represents phenyl    optionally substituted by one or more groups selected from halo, CH₃    and OCH₃ and A represents phenyl, then A is substituted by one or    more R^(4a) substituents;-   (vi) when L¹ represents a bond, L² represents NH and A represents    2,3-dichlorophenyl then B does not represent    3,4,5-trihydroxytetrahydropyran-2-carboxylic acid;-   (vii) when L¹ represents a bond, L² represents a bond, B represents    unsubstituted furanyl and A represents furanyl, then A is    substituted by one or more R^(4a) substituents;-   (viii) when A is a phenyl ring bearing substituents R^(4a) at both    meta-positions and is unsubstituted at the para-position, relative    to the point of attachment of A to the rest of the molecule, then B    can be unsubstituted phenyl.

Still further compounds of formula I may be novel. In this respect,still further aspects of the invention relate to compounds of formula I(or A1 or, particularly, Ia, Ib, Ic, Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb,Izb, Ixb1, Iyb1, Izb1, Iyc, Ixd, Iyd or Izd (or, in certain embodiments,of formula I, Ia, Ib or Ic)) as described hereinbefore, wherein when L¹represents a bond or CH₂, L² represents a bond or NH, then at least oneof A and B is not phenyl.

Still further compounds of formula I may be novel. Thus, according to afurther aspect of the invention, there is provided a compound of formulaI, which relate to compounds of formula I in which:

-   (1) R¹ represents H;-   (2) L¹ represents CH₂, NR^(3a), S(O)_(p) or, particularly, a direct    bond, O, or C(O);-   (3) L² represents CH₂, S(O)_(p), or, particularly, a direct bond, O,    or C(O);-   (4) A represents a group selected from cyclopentyl, dihydrofuranyl    (e.g 2,3-dihydrofuranyl, 2,5-dihydrofuranyl),    4,5-dihydro-1H-maleimido, dioxanyl, furazanyl, hydantoinyl,    imidazolyl, isoxazolyl, isoxazolidinyl, isothiaziolyl, oxadiazolyl,    oxazolyl, pyrazolyl, pyrrolinyl (e.g. 3-pyrrolinyl), pyrrolyl,    pyrrolidinonyl, sulfolanyl, 3-sulfolenyl, tetrahydrofuranyl,    tetramethylenesulfoxide, tetrazolyl, thiadiazolyl, thiazolyl,    thiazolidinyl, thienyl, triazolyl, particularly    2-azabicyclo[4.1.0]heptanyl, 1-azabicyclo-[2.2.2]octanyl,    benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzodioxanyl,    benzofuranyl, benzofurazanyl, benzo[c]isoxazolidinyl,    benzomorpholinyl, 2,1,3-benzoxadiazolyl, benzoxazinyl (including    3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolidinyl, benzopyrazolyl,    benzo[e]pyrimidine, 2,1,3-benzothiadiazolyl, benzothiazolyl,    benzothienyl, benzotriazolyl, carbazolyl, chromanyl, chromenyl,    cinnolinyl, (1Z,2Z,4Z,6Z,8Z)-cyclodecapentaenyl, cyclohexyl,    cyclopentenyl, decahydroisoquinolenyl, 2,3-dihydrobenzimidazolyl,    1,3-dihydrobenzo-[c]furanyl, 1,3-dihydro-2,1-benzisoxazolyl,    dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl),    2,3-dihydropyrrolo[2,3-b]pyridinyl, dioxolanyl,    hexahydropyrimidinyl, imidazo[2,3-b]thiazolyl, indanyl, indazolyl,    indenyl, indolinyl, isobenzofuranyl, isochromanyl, isoindolinyl,    isoindolyl, isothiochromanyl, ketopiperidinyl (e.g.    2-ketopiperidinyl, 3-ketopiperidinyl or 4-ketopiperidinyl),    naphtho[1,2-b]furanyl, naphthyridinyl (including 1,6-naphthyridinyl    or, particularly, 1,5-naphthyridinyl and 1,8-naphthyridinyl), 1,2-    or 1,3-oxazinanyl, oxazolidinyl, phenazinyl, phenothiazinyl,    phthalazinyl, piperazinyl, pteridinyl, purinyl, pyranyl,    pyridazinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[5,1-b]pyridinyl,    pyrrolo[2,3-c]pyridinyl, quinazolinyl, quinolizinyl, quinoxalinyl,    4,5,6,7-tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzopyrazolyl,    5,6,7,8-tetrahydrobenzo-[e]pyrimidine, tetrahydroisoquinolinyl    (including 1,2,3,4-tetrahydroisoquinolinyl and    5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including    1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl),    tetrahydropyranyl, tetrahydropyridinyl (e.g.    3,4,5,6-tetrahydropyridinyl), 1,2,3,4-tetrahydropyrimidinyl,    3,4,5,6-tetrahydropyrimidinyl, tetrahydrothiophenyl,    thieno[5,1-c]pyridinyl, thiochromanyl, thiophenetyl, triazinanyl,    1,3,4-triazolo[2,3-b]pyrimidinyl, particularly, benzoxazolyl,    benzodioxolyl, 2,3-dihydrobenzo[b]furanyl, cyclohexyl, furanyl,    imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, indolyl,    isoquinolinyl, morpholinyl, napthalenyl (e.g. 1-napthalenyl,    2-napthalenyl, 1,2,3,4-tetrahydronaphthyl), piperidinyl,    pyrimidinyl, pyrrolidinyl pyrrolo[1,5-a]pyridinyl, pyrazinyl,    pyridinonyl (such as 1-1H-pyridin-2-onyl, 3-1H-pyridin-2-onyl,    4-1H-pyridin-2-onyl, 6-1H-pyridin-2-onyl, or, particularly,    4-pyridinonyl), quinolinyl, more particularly, pyridinyl (e.g.    2-pyridinyl, 3-pyridinyl, 4-pyridinyl), which are optionally    substituted by one or more R^(4a) or R^(4b) substituents, as    appropriate, and phenyl substituted by one or more R^(4a)    substituents;-   (5) B represents piperidine or, particularly, phenyl substituted by    one or more R^(4c) substituents;-   (6) R^(4c) represents, independently at each occurrence,    -   Cl or, particularly, Br, F, I,    -   CN,    -   C₂₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, which latter three        groups are optionally substituted by one or more substituents        selected from halo, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl (which latter three groups are optionally substituted by        one or more substituents selected from OH, ═O, halo, C₁₋₄ alkyl        and C₁₋₄ alkoxy), OR^(5a), S(O)_(q)R^(5b),        S(O)₂N(R^(5c))(R^(5d)), N(R^(5e))S(O)₂R^(5f), N(R^(5g))(R^(5h)),        B¹—C(G¹)-B²—R^(5i), aryl and Het¹,    -   Cy³, which Cy³ group is optionally substituted by one or more        substituents selected from halo, nitro, CN, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl (which latter three groups are optionally        substituted by one or more substituents selected from OH, ═O,        halo, C₁₋₄ alkyl and C₁₋₄ alkoxy), OR^(6a), S(O)_(q)R^(6b),        S(O)₂N(R^(6c))(R^(6d)), N(R^(6e))S(O)₂R^(6f), N(R^(6g))(R^(6h)),        B³—C(G¹)-B⁴—R^(6i), aryl and Het²,    -   Het^(a), which Het^(a) group is optionally substituted by one or        more substituents selected from halo, nitro, CN, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl (which latter three groups are        optionally substituted by one or more substituents selected from        OH, ═O, halo, C₁₋₄ alkyl and C₁₋₄ alkoxy), OR^(7a),        S(O)_(q)R^(7b), S(O)₂N(R^(7c))(R^(7d)), N(R^(7e))S(O)₂R^(7f),        N(R^(7g))(R^(7h)), B⁵—C(G¹)-B⁶—R^(7i), aryl and Het³,    -   OR⁸,    -   meta- or ortho-methoxy relative to the point of attachment of B        to the rest of the molecule;    -   S(O)_(r)R^(9a),    -   S(O)₂N(R^(9b))(R^(9c)),    -   N(R^(9d))S(O)₂R^(9e),    -   N(R^(9f))(R^(9g))    -   B⁷—C(G¹)-B⁸—R^(9h),    -   ═O,    -   ═S,    -   or when two R^(4c) groups are attached to the same carbon atom        in a non-aromatic portion of a Cy¹, Het^(A), Cy² or Het^(B)        group, they may form, together with the carbon atom to which        they are attached, a saturated or unsaturated 3 to 6-membered        ring, which ring optionally contains one to three heteroatoms        selected from O, S and N, and which ring is optionally        substituted by one or more R^(a) substituents;-   (7) R⁸ represents, independently at each occurrence,    -   H,    -   Cy³, Het^(a), aryl^(a), C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,        C₃₋₈ cycloalkyl, which latter seven groups are optionally        substituted by one or more substituents selected from halo, —CN,        C₃₋₆ cycloalkyl, aryl, Het⁴, —C(O)OR¹⁰, —C(O)R¹¹,        —C(O)N(R^(N1))(R^(N2)), S(O)_(r)R^(9aa),        S(O)₂N(R^(9ba))(R^(9ca)), N(R^(9da))S(O)₂R^(9ea) and        N(R^(9fd))(R^(9ga)).

Further embodiments of the invention, include those in which L¹represents a direct bond, O, NH, S, SO₂ or C(O) and L² represents adirect bond (e.g. L¹ represents a direct bond or O, and L² represents adirect bond.)

Still further compounds of formula I may be novel. Thus, according to afurther aspect of the invention, there is provided a compound of formulaI, which relate to compounds of formula I in which:

-   (1) L¹ represents a direct bond, O, NR^(3a), S(O)_(p) or C(O);-   (2) L² represents a direct bond, O, S(O)_(p), NR, CH₂ or C(O);-   (3) B represents a group, selected from 2-azabicyclo[4.1.0]heptanyl,    1-azabicyclo-[2.2.2]octanyl, benzimidazolyl, benzisothiazolyl,    benzisoxazolyl, benzodioxanyl, benzodioxolyl, benzofurazanyl,    benzo[c]isoxazolidinyl, 2,1,3-benzoxadiazolyl, benzoxazolidinyl,    benzoxazolyl, benzopyrazolyl, 2,1,3-benzothiadiazolyl,    benzothiazolyl, benzothienyl, benzotriazolyl, cyclopentyl,    cyclohexyl, cyclopentenyl, cyclohexenyl, 2,3-dihydrobenzimidazolyl,    dihydrofuranyl (e.g. 2,3-dihydrofuranyl, 2,5-dyhdrofuranyl),    2,3-dihydrobenzo[b]furanyl, 1,3-dihydrobenzo-[c]furanyl,    dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl),    4,5-dihydro-1H-maleimido, 1,3-dihydro-2,1-benzisoxazolyl    2,3-dihydropyrrolo[2,3-b]pyridinyl, dioxanyl, dioxolanyl, furazanyl,    hexahydropyrimidinyl, hydantoinyl, imidazolyl,    imidazo[1,2-a]pyridinyl, imidazo[2,3-b]thiazolyl, indanyl, indenyl,    indolinyl, isobenzofuranyl, isoindolinyl, isoindolyl, isothiaziolyl,    isoxazolyl, isoxazolidinyl, ketopiperidinyl (e.g. 2-ketopiperidinyl,    3-ketopiperidinyl or 4-ketopiperidinyl), morpholinyl, oxadiazolyl,    1,2- or 1,3-oxazinanyl, oxazolidinyl, oxazolyl, piperidinyl (e.g.    piperidin-1-yl or, particularly, piperidin-2-yl, piperidin-3-yl,    piperidin-4-yl, piperidin-5-yl or piperidin-6-yl), piperazinyl,    phthalazinyl, pteridinyl, purinyl, pyranyl, pyridazinyl,    pyrrolidinonyl, pyrrolinyl (e.g. 3-pyrrolinyl), pyrrolyl,    pyrrolo[2,3-b]pyridinyl, pyrrolo[5,1-b]pyridinyl,    pyrrolo[2,3-c]pyridinyl, sulfolanyl, 3-sulfolenyl,    tetrahydrofuranyl, tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl,    1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl,    tetrahydrothiophenyl, 4,5,6,7-tetrahydrobenzimidazolyl,    4,5,6,7-tetrahydrobenzopyrazolyl, tetramethylenesulfoxide,    tetrazolyl, thiazolidinyl, thiazolyl, thienyl,    thieno[5,1-c]pyridinyl, thiophenethyl, triazinanyl, triazoly,    1,3,4-triazolo[2,3-b]pyrimidinyl, more particularly, benzofuranyl,    indazolyl, indolyl, pyrazinyl, pyrazolyl, pyridinyl (e.g.    2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyridinonyl, pyrimidinyl and    pyrrolo[1,5-a]pyridinyl, wherein B is optionally substituted by one    or more R^(4c) or R^(4d) substituents, as appropriate.

The invention encompasses (in respect of the invention described herein)embodiments in which the compound of formula A1 or, particularly, I, Ia,Ib, Ic, Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Iyc,Ixd, Iyd or Izd (or, in certain embodiments, of formula I, Ia, Ib or Ic)has definitions of A, B, L¹, L² and R¹ that are derived from anymutually compatible combination of any of the substituent definitionslisted above in respect of compounds of formulae A1 or, particularly, I,Ia, Ib, Ic, Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1,Iyc, Ixd, Iyd or Izd (or, in certain embodiments, of formula I, Ia, Ibor Ic).

In accordance with the invention, compounds of formula I (e.g. formulaA1) may be administered alone (i.e. as a monotherapy, such as amonotherapy of a condition or disorder ameliorated by inhibition of theA₁ or, particularly, A_(2a) receptor). In alternative embodiments of theinvention, however, compounds of formula I (e.g. formula A1) may beadministered in combination with another therapeutic agent (e.g. anothertherapeutic agent for the treatment of a condition or disorderameliorated by inhibition of the A₁ or, particularly, A_(2a) receptor).

Thus further aspects of the invention relate to the following.

-   (a) A compound of formula I (e.g. formula A1), as hereinbefore    defined, and another therapeutic agent for use in the treatment of a    condition or disorder ameliorated by the inhibition of the A₁ or,    particularly, the A_(2a) receptor.    -   In this aspect of the invention, the compound of formula I, as        hereinbefore defined, may be administered sequentially,        simultaneously or concomitantly with the other therapeutic agent-   (b) A compound of formula I (e.g. formula A1), as hereinbefore    defined, for use in the treatment of a condition or disorder    ameliorated by the inhibition of the A₁ or, particularly, the A_(2a)    receptor, wherein the compound of formula I is administered    sequentially, simultaneously or concomitantly with another    therapeutic agent.-   (c) Use of a compound of formula I (e.g. formula A1), as    hereinbefore defined, and another therapeutic agent for the    preparation of a medicament for the treatment of a condition or    disorder ameliorated by the inhibition of the A₁ or, particularly,    the A_(2a) receptor, wherein the compound of formula I is    administered sequentially, simultaneously or concomitantly with the    other therapeutic agent.-   (d) Use of a compound of formula I (e.g. formula A1), as    hereinbefore defined, for the preparation of a medicament for the    treatment of a condition or disorder ameliorated by the inhibition    of the A₁ receptor or, particularly, the A_(2a) receptor, wherein    the medicament is administered in combination with another    therapeutic agent.-   (e) A method of treatment of a disorder or condition ameliorated by    antagonising the A₁ receptor or, particularly, the A_(2a) receptor,    which method comprises the administration of an effective amount of    a compound of formula I (e.g. formula A1), as hereinbefore defined,    and another therapeutic agent to a patient in need of such    treatment.-   (f) A combination product comprising    -   (A) a compound of formula I (e.g. formula A1), as hereinbefore        defined, and    -   (B) another therapeutic agent,    -   wherein each of components (A) and (B) is formulated in        admixture with a pharmaceutically-acceptable adjuvant, diluent        or carrier.-   (g) A combination product as defined at (f) above for use in the    treatment of a condition or disorder ameliorated by the inhibition    of the A₁ receptor or, particularly, the A_(2a) receptor.-   (h) The use of a combination product as defined at (f) above for the    manufacture of a medicament for the treatment of a condition or    disorder ameliorated by the inhibition of the A₁ receptor or,    particularly, the A_(2a) receptor.-   (i) A method of treatment of a disorder or condition ameliorated by    antagonising the A₁ receptor or, particularly, the A_(2a) receptor,    which method comprises the administration of an effective amount of    a combination product as defined at (f) above.

When used herein, the term “another therapeutic agent” includesreferences to one or more (e.g. one) therapeutic agents (e.g. onetherapeutic agent) that are known to be useful for (e.g. that are knownto be effective in) the treatment of: heart failure (such as acutedecompensated heart failure and congestive heart failure); kidneyfailure (e.g. caused by heart failure); oedema; cancer (such asprostate, rectal, renal, ovarian, endometrial, thyroid, pancreatic,particularly breast, colon, bladder, brain, glia, melanoma, pineal glandcancer and, more particularly, Lewis lung carcinoma; diabetes; diarrhea;macular degeneration (such as macular degeneration caused byangiogenesis (e.g. retinal angiogenesis); or particularly a disease ofthe central nervous system such as depression, a cognitive functiondisease, a neurodegenerative disease (such as Parkinson's disease,Huntington's disease, Alzheimer's disease, amyotrophic lateralsclerosis) and psychoses; an attention related disorder (such asattention deficit disorder (ADD) and attention deficit hyperactivitydisorder (ADHD)); extra pyramidal syndrome (e.g. dystonia, akathisia,pseudoparkinsonism and tardive dyskinesia); a disorder of abnormalmovement (such as restless leg syndrome (RLS) and periodic limb movementin sleep (PLMS)); cirrhosis; liver fibrosis; fatty liver; dermalfibrosis (e.g. in diseases such as scleroderma); a sleep disorder;stroke; and addictive behaviour. In particular embodiments of theinvention that may be mentioned, the one or more other therapeuticagents do not exert their therapeutic effect by way of binding to anadenosine receptor (e.g. the A_(2a) receptor).

Particular other therapeutic agents that may be mentioned include, forexample, levodopa (L-DOPA), dopamine agonists (e.g. pramipexole,ropinirole or rotigotine), monoamine oxidase B inhibitors (e.g.selegiline or rasagiline), catechol O-methyl transferase inhibitors(e.g. entacapone or tolcapone), amantadine, acetylcholinesteraseinhibitors (e.g. donepezil, rivastigmine or galantamine) and glutamateinhibitors (e.g. memantine).

When used herein, the term “administered sequentially, simultaneously orconcomitantly” includes references to:

-   -   administration of separate pharmaceutical formulations (one        containing the compound of formula I and one or more others        containing the one or more other therapeutic agents); and    -   administration of a single pharmaceutical formulation containing        the compound of formula I and the other therapeutic agent(s).

The combination product described above provides for the administrationof component (A) in conjunction with component (B), and may thus bepresented either as separate formulations, wherein at least one of thoseformulations comprises component (A) and at least one comprisescomponent (B), or may be presented (i.e. formulated) as a combinedpreparation (i.e. presented as a single formulation including component(A) and component (B)).

Thus, there is further provided:

-   (I) a pharmaceutical formulation including a compound of formula I    (e.g. formula A1), as hereinbefore defined and another therapeutic    agent, in admixture with a pharmaceutically-acceptable adjuvant,    diluent or carrier (which formulation is hereinafter referred to as    a “combined preparation”); and-   (II) a kit of parts comprising components:    -   (i) a pharmaceutical formulation including a compound of formula        I (e.g. formula A1), as hereinbefore defined, in admixture with        a pharmaceutically-acceptable adjuvant, diluent or carrier; and    -   (ii) a pharmaceutical formulation including another therapeutic        agent, in admixture with a pharmaceutically-acceptable adjuvant,        diluent or carrier,    -   which components (i) and (ii) are each provided in a form that        is suitable for administration in conjunction with the other.

Component (i) of the kit of parts is thus component (A) in admixturewith a pharmaceutically-acceptable adjuvant, diluent or carrier.Similarly, component (ii) is component (B) in admixture with apharmaceutically-acceptable adjuvant, diluent or carrier.

Compounds of formula I (e.g. formula A1) may be administered by anysuitable route, but may particularly be administered orally,intravenously, intramuscularly, cutaneously, subcutaneously,transmucosally (e.g. sublingually or buccally), rectally, transdermally,nasally, pulmonarily (e.g. tracheally or bronchially), topically, by anyother parenteral route, in the form of a pharmaceutical preparationcomprising the compound in a pharmaceutically acceptable dosage form.Particular modes of administration that may be mentioned include oral,intravenous, cutaneous, subcutaneous, nasal, intramuscular orintraperitoneal administration

Compounds of formula I (e.g. formula A1) will generally be administeredas a pharmaceutical formulation in admixture with a pharmaceuticallyacceptable adjuvant, diluent or carrier, which may be selected with dueregard to the intended route of administration and standardpharmaceutical practice. Such pharmaceutically acceptable carriers maybe chemically inert to the active compounds and may have no detrimentalside effects or toxicity under the conditions of use. Suitablepharmaceutical formulations may be found in, for example, Remington TheScience and Practice of Pharmacy, 19th ed., Mack Printing Company,Easton, Pa. (1995). For parenteral administration, a parenterallyacceptable aqueous solution may be employed, which is pyrogen free andhas requisite pH, isotonicity, and stability. Suitable solutions will bewell known to the skilled person, with numerous methods being describedin the literature. A brief review of methods of drug delivery may alsobe found in e.g. Langer, Science (1990) 249, 1527.

Otherwise, the preparation of suitable formulations may be achievedroutinely by the skilled person using routine techniques and/or inaccordance with standard and/or accepted pharmaceutical practice.

The amount of compound of formula I (e.g. formula A1) in anypharmaceutical formulation used in accordance with the present inventionwill depend on various factors, such as the severity of the condition tobe treated, the particular patient to be treated, as well as thecompound(s) which is/are employed. In any event, the amount of compoundof formula I in the formulation may be determined routinely by theskilled person.

For example, a solid oral composition such as a tablet or capsule maycontain from 1 to 99% (w/w) active ingredient; from 0 to 99% (w/w)diluent or filler; from 0 to 20% (w/w) of a disintegrant; from 0 to 5%(w/w) of a lubricant; from 0 to 5% (w/w) of a flow aid; from 0 to 50%(w/w) of a granulating agent or binder; from 0 to 5% (w/w) of anantioxidant; and from 0 to 5% (w/w) of a pigment. A controlled releasetablet may in addition contain from 0 to 90% (w/w) of arelease-controlling polymer.

A parenteral formulation (such as a solution or suspension for injectionor a solution for infusion) may contain from 1 to 50% (w/w) activeingredient; and from 50% (w/w) to 99% (w/w) of a liquid or semisolidcarrier or vehicle (e.g. a solvent such as water); and 0-20% (w/w) ofone or more other excipients such as buffering agents, antioxidants,suspension stabilisers, tonicity adjusting agents and preservatives.

Depending on the disorder, and the patient, to be treated, as well asthe route of administration, compounds of formula I (e.g. formula A1)may be administered at varying therapeutically effective doses to apatient in need thereof.

However, the dose administered to a mammal, particularly a human, in thecontext of the present invention should be sufficient to effect atherapeutic response in the mammal over a reasonable timeframe. Oneskilled in the art will recognize that the selection of the exact doseand composition and the most appropriate delivery regimen will also beinfluenced by inter alia the pharmacological properties of theformulation, the nature and severity of the condition being treated, andthe physical condition and mental acuity of the recipient, as well asthe potency of the specific compound, the age, condition, body weight,sex and response of the patient to be treated, and the stage/severity ofthe disease.

Administration may be continuous or intermittent (e.g. by bolusinjection). The dosage may also be determined by the timing andfrequency of administration. In the case of oral or parenteraladministration the dosage can vary from about 0.01 mg to about 1000 mgper day of a compound of formula I (e.g. formula A1).

In any event, the medical practitioner, or other skilled person, will beable to determine routinely the actual dosage, which will be mostsuitable for an individual patient. The above-mentioned dosages areexemplary of the average case; there can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

As mentioned above, compounds of formula A1 or, particularly, Ix, Iy,Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Iyc, Ixd, Iyd or Izd(or, particularly, formula I, Ia, Ib or Ic) may bind selectively to A₁or, particularly, A_(2a) receptors, and may therefore have utility asdiagnostic agents for determining the presence and/or location (eitherin vivo or in vitro) of adenosine A₁ or, particularly, A_(2a) receptors.

Thus, according to a further aspect of the invention there is provided amethod (e.g. an in vivo or, particularly, an ex vivo method) ofdetermining the presence and/or location of adenosine A_(2a) receptorsin a tissue sample, said method comprising contacting the tissue samplewith a compound of formula A1 or, particularly, Ix, Iy, Iz, Ixa, Iya,Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Iyc, Ixd, Iyd or Izd (or,particularly, formula I, la, Ib or Ic) and then detecting by avisualising method the location of the compound of formula I in thesample.

Visualising methods that may be mentioned include spectroscopicdetection methods (e.g. fluorescence detection, magnetic resonanceimaging, etc.) or, when the compound of formula I is isotopicallylabelled or enriched with a radioisotope (such as ³H, ¹¹C, ³⁵S, ¹⁸F, or¹²⁵I), radioactivity detection methods (e.g. alpha-, beta- orgamma-detection by standard autoradiography, phosphor or scintillationmethods known to those skilled in the art, or positron emissiontomography (which latter method may be employed, for example, when thecompound of formula I is isotopically labelled or enriched with ¹¹C, or,particularly, ¹³F)).

The aspects of the invention described herein (e.g. the above-mentionedcompounds, combinations, methods and uses) may have the advantage that,in the treatment of the conditions described herein, they may be moreconvenient for the physician and/or patient than, be more efficaciousthan, be less toxic than, have better selectivity over, have a broaderrange of activity than, be more potent than, produce fewer side effectsthan, or may have other useful pharmacological properties over, similarcompounds, combinations, methods (treatments) or uses known in the priorart for use in the treatment of those conditions or otherwise.

Side effects that may be mentioned in this respect include side effectscaused by A₃ receptor antagonism (such as an increased propensity fortissue damage following ischaemia (e.g. in the CNS, heart, kidney, lungand eye), increased reperfusion injury, increased neurodegeneration inresponse to hypoxia, potentially deleterious effects on motor functionor pain thresholds, immunosuppression or immunostimulation).

Compounds of formula I may be known and/or may be commerciallyavailable. Other compounds of formula I (e.g. that are not commerciallyavailable) may be prepared in accordance with techniques that are wellknown to those skilled in the art, for example as described hereinafter.

According to a further aspect of the invention there is provided aprocess for the preparation of a compound of formula I which processcomprises:

(ia) for compounds of formula I in which R¹ represents CH₂—R^(1a),wherein R^(1a) represents a C₁₋₅ alkyl optionally substituted by one ormore halo atoms, reaction of a compound of formula I in which R¹represents H, with a compound of formula IIa,

wherein R^(1a) represents H or a C₁₋₅ alkyl which may be optionallysubstituted by one or more halo atoms, followed by reduction of theresulting imine by a suitable reducing agent (e.g. LiBH₄, NaBH₄,NaBH(OAc)₃, LiAlH₄), under reaction conditions well known to thoseskilled in the art, for example under such conditions that the two stepsmay be performed with or without the separation or purification of thereaction mixture;

-   (ib) for compounds of formula I in which R¹ represents C₁₋₆ alkyl    optionally substituted by one or more of halo OR^(2a) or    NR^(2b)R^(2c), reaction of a compound of formula I in which R¹    represents H, with a compound of formula IIb,    L^(xxa)-R^(1x)  IIb    wherein L^(xaa) represents a suitable leaving group (such as chloro,    bromo, or preferably iodo) and R^(1x) represents C₁₋₆ alkyl    optionally substituted by one or more of halo OR^(2a) or    NR^(2b)R^(2c), under reaction conditions known to those skilled in    the art, for example in the presence of an appropriate base (such as    Hunig's base, triethylamine, pyridine), in a suitable solvent (e.g.    pyridine, triethylamine, dichloromethane, tetrahydrofuran) and at a    suitable temperature (e.g. from room temperature to about 180° C.);-   (ii) for compounds of formula I in which L¹ represents a direct    bond,    -   (a) reaction of a compound of formula III,

wherein L^(x1a) represents a metal halide (for example a zinc halide(e.g. —ZnCl) or a magnesium halide (e.g. —MgBr)), —Sn(R^(x1))₃, anorganoboronic acid (e.g. an alkyl-cyclotriboroxane derivative or,particularly, —B(OH)₂ or —B(OR^(x1))₂), or an organosilane (e.g.—Si(OEt)₃), wherein each R^(x1) mentioned herein independentlyrepresents a C₁₋₆ alkyl group, or, in the case of —B(OR^(x1))₂, the twoR^(x1) groups may be linked together to form a 4- to 6-membered cyclicgroup (such as a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group), andL², B, and R¹ are as defined hereinbefore, with a compound of formulaIV,A-X^(1a)  IVwherein X^(1a) represents a suitable leaving group (such as chloro,bromo, or preferably iodo), and A is as defined hereinbefore, underreaction conditions known to those skilled in the art, for example inthe presence of an appropriate metal catalyst (or a salt or complexthereof, such as Cu, Cu(OAc)₂, CuI (or CuI/diamine complex), coppertris(triphenyl-phosphine)bromide, Pd(OAc)₂, Pd₂(dba)₃ or NiCl₂) and anoptional additive (such as Ph₃P,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, xantphos, NaI or anappropriate crown ether such as 18-crown-6-benzene), in the presence ofan appropriate base (such as NaH, Et₃N, pyridine,N,N′-dimethylethylenediamine, triethanolamine. N-methyldiethanolamine,N,N-diisopropylethanolamine, triisopropanolamine, Na₂CO₃, K₂CO₃, K₃PO₄,Cs₂CO₃, t-BuONa or t-BuOK or a mixture thereof, optionally in thepresence of 4 Å molecular sieves), in a suitable solvent (e.g.dichloromethane, dioxane, toluene, ethanol, isopropanol,dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether,water, dimethylsulfoxide, acetonitrile, propionitrile,dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran, diethyl etheror a mixture thereof) and at a suitable temperature (e.g. from roomtemperature to about 180° C.);

-   -   (b) reaction of a compound of formula V,

wherein X^(1b) represents a suitable leaving group (such as chloro,bromo, or preferably iodo), and L², B, and R¹ are as definedhereinbefore, with a compound of formula VI,A-L^(x1b)  VIwherein L^(x1b) represents a metal halide (for example a zinc halide(e.g. —ZnCl) or a magnesium halide (e.g. —MgBr)), —Sn(R^(x1))₃, anorganoboronic acid (e.g. an alkyl-cyclotriboroxane derivative or,particularly, —B(OH)₂ or —B(OR^(x1))₂), or an organosilane (e.g.—Si(OEt)₃), wherein each R^(x1) is a defined above, and A is as definedhereinbefore, under reaction conditions known to those skilled in theart, for example such as those described in respect of process step(ii)(a) above;

-   (iii) for compounds of formula I in which L¹ represents —NR^(3a)—,    -   (a) reaction of a compound of formula VII,

wherein X^(2a) represents a suitable leaving group (such as chloro,bromo, iodo or a sulfonate group (e.g. —OS(O)₂CF₃, —OS(O)₂CH₃ or—OS(O)₂PhMe)), and L², B, and R¹ are as defined hereinbefore with acompound of formula VIII,A-NHR^(3a)  VIIIwherein A and R^(3a) are as defined hereinbefore, under reactionconditions known to those skilled in the art, for example in thepresence of an appropriate base (such as NaH, Et₃N, pyridine,N,N′-dimethylethylenediamine, Na₂CO₃, K₂CO₃, K₃PO₄, Cs₂CO₃, t-BuONa ort-BuOK or a mixture thereof, optionally in the presence of 4 Å molecularsieves), optionally in the presence of a suitable solvent (e.g.dichloromethane, dioxane, toluene, ethanol, isopropanol,dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether,water, dimethylsulfoxide, acetonitrile, dimethylacetamide,N-methylpyrrolidinone, tetrahydrofuran or a mixture thereof) and at asuitable temperature (e.g. from room temperature to about 180° C.);

-   -   (b) reaction of a compound of formula IX,

wherein R^(3a), L², B, and R¹ are as defined hereinbefore, with acompound of formula X,A-X^(2b)  Xwherein X^(2b) represents a suitable leaving group (such as chloro,bromo, iodo or a sulfonate group (e.g. —OS(O)₂CF₃, —OS(O)₂CH₃ or—OS(O)₂PhMe)), and A represents Cy¹ or Het^(A), as defined hereinbefore,except that the Cy¹ or Het^(A) group contains a fully saturated carbonatom that is attached to X^(2b), under reaction conditions known tothose skilled in the art, for example such as those described in respectof process step (iii)(a) above;

-   -   (c) reaction of a compound of formula IX as defined above, with        a compound of formula XI,        A-L^(x2a)  XI        wherein L^(x2a) represents a suitable leaving group (such as        chloro, bromo, iodo or a sulfonate group (e.g. —OS(O)₂CF₃,        —OS(O)₂CH₃ or —OS(O)₂PhMe), —B(OH)₂ or —B(OR^(x1))₂, in which        each R^(x1) is as defined above, and A represents Cy¹ or        Het^(A), as defined hereinbefore, except that Cy¹ or Het^(A)        contains an aromatic ring that is attached to L^(x2a) via a        carbon atom, under reaction conditions known to those skilled in        the art, for example in the presence of an appropriate metal        catalyst (or a salt or complex thereof, such as Cu, Cu(OAc)₂,        CuI (or CuI/diamine complex), copper        tris(triphenyl-phosphine)bromide), in a suitable solvent (e.g.        dichloromethane, dioxane, toluene, ethanol, isopropanol,        dimethylformamide, ethylene glycol, ethylene glycol dimethyl        ether, water, dimethylsulfoxide, acetonitrile,        dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran or a        mixture thereof), and at a suitable temperature (e.g. from room        temperature to about 180° C.), e.g. as described in Quach et al.        Org. Lett., 2003, 5, 4397-4400 or Wolfe et al. 2004. Org.        Synth.: Coll. Vol. 10: 423;    -   (d) reaction of a compound of formula XII,

wherein L^(x2b) represents a suitable leaving group (such as chloro,bromo, iodo or a sulfonate group (e.g. —OS(O)₂CF₃, —OS(O)₂CH₃ or—OS(O)₂PhMe), —B(OH)₂ or —B(OR^(x1))₂ in which each R^(x1) is as definedabove, and L², B, and R¹ are as defined hereinbefore, with a compound offormula VIII as defined above, under reaction conditions known to thoseskilled in the art, for example such as those described in respect ofprocess step (iii)(c) above;

-   (iv) for compounds of formula I in which L¹ represents —O— or —S—,    -   (a) reaction of a compound of formula VII as defined above, with        a compound of formula XIII,        A-Q^(a)-H  XIII        wherein Q^(a) is O or S, and A is as defined hereinbefore, under        reaction conditions known to those skilled in the art, for        example the reaction may be performed at a suitable temperature        (e.g. from room temperature to about 180° C.), in the presence        of a suitable base (e.g. caesium carbonate, sodium hydride,        sodium bicarbonate, potassium carbonate, pyrrolidinopyridine,        pyridine, triethylamine, tributylamine, trimethylamine,        dimethylaminopyridine, diisopropylamine, diisopropylethylamine,        1,8-diazabicycbo[5.4.0]undec-7-ene, sodium hydroxide,        N-ethyldiisopropylamine,        N-(methylpolystyrene)-4-(methylamino)pyridine, potassium        bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide,        potassium tert-butoxide, lithium diisopropylamide, lithium        2,2,6,6-tetramethylpiperidine or mixtures thereof), or        alternatively in the presence of a suitable coupling agent (such        as a dialkylazodicarboxylate (e.g. diethylazodicarboxylate)        together with a trialkyl or triaryl phosphine (e.g. PPh₃)), and        an appropriate solvent (e.g. dimethylsulfoxide, tetrahydrofuran,        pyridine, toluene, dichloromethane, chloroform, acetonitrile,        dimethylformamide, trifluoromethylbenzene, dioxane or        triethylamine);    -   (b) reaction of a compound of formula XIV,

wherein Q^(b) is O or S, and L², B and R¹ are as defined hereinbefore,with a compound of formula X as defined above, under reaction conditionsknown to those skilled in the art, for example such as those describedin respect of process step (iv(a) above;

-   (v) for compounds of formula I in which L¹ represents —O— and A    represents Cy¹ or Het^(A) as defined hereinbefore, except that the    Cy¹ or Het^(A) group is directly attached to the rest of the    molecule via a fully saturated carbon atom, reaction of a compound    of formula XIII, wherein Q^(a) is O and A is as defined    hereinbefore, with a compound of formula XIV wherein Q^(b) is O and    L², B and R¹ are as defined hereinbefore, under reaction conditions    known to those skilled in the art, for example the reaction may be    performed at a suitable temperature (e.g. from room temperature to    about 180° C.), in the presence of a suitable coupling agent (such    as a dialkylazodicarboxylate (e.g. diethylazodicarboxylate) together    with a trialkyl or triaryl phosphine (e.g. PPh₃)), and an    appropriate solvent (e.g. tetrahydrofuran, dimethylsulfoxide,    pyridine, toluene, dichloromethane, chloroform, acetonitrile,    dimethylformamide, trifluoromethylbenzene, dioxane or    triethylamine);-   (vi) for compounds of formula I in which L¹ represents —S(O)— or    —S(O)₂—, oxidation of a compound of formula I in which L¹ represents    —S—, in the presence of a suitable oxidising agent, (for example    meta-chloroperoxybenzoic acid, KMnO₄, t-butylammoniumperiodate    and/or potassium peroxymonosulfate (e.g. Oxone®)). In order to    provide selective oxidisation to provide either compounds of formula    I in which L¹ represents —S(O)— or —S(O)₂—, the skilled person will    appreciate that the length of time (and the number of equivalents of    the oxidising agent) or the use of certain oxidising agents may    provide for better selectivity. For example, for the formation of    compounds of formula I in which L¹ represents —S(O)—, the oxidising    agent of choice is preferably t-butylammoniumperiodate (and    preferably one equivalent, or a slight excess, is employed). Such a    reaction may be performed in the presence of a suitable solvent such    as dichloromethane, and optionally in the presence of a catalyst    such as 5,10,15,20-tetraphenyl-21H,23H-porphine iron(III)chloride,    under an inert atmosphere. For the formation of compounds of formula    I in which L¹ represents —S(O)₂—, the oxidising agent is preferably    potassium peroxymonosulfate (e.g. Oxone®), which reaction may be    performed in the presence of a suitable solvent such as    tetrahydrofuran;-   (vii) for compounds of formula I in which L² represents a direct    bond,    -   (a) reaction of a compound of formula XV,

wherein L^(x3a) represents a metal halide (for example a zinc halide(e.g. —ZnCl) or a magnesium halide (e.g. —MgBr)), —Sn(R^(x1))₃, anorganoboronic acid (e.g. an alkyl-cyclotriboroxane derivative or,particularly, —B(OH)₂ or —B(OR^(x1))₂), or an organosilane (e.g.—Si(EtO)₃), in which each R^(x1) is as defined above, and L¹, A, and R¹are as defined hereinbefore, with a compound of formula XVI,B—X^(3a)  XVIwherein X^(3a) represents a suitable leaving group such as chloro,bromo, or preferably iodo, and B is as defined hereinbefore, underreaction conditions known to those skilled in the art, for example suchas those described in respect of process step (ii)(a) above;

-   -   (b) reaction of a compound of formula XVII,

wherein X^(3b) represents a suitable leaving group such as chloro,bromo, or preferably iodo, and L¹, A, and R¹ are as definedhereinbefore, with a compound of formula XVIII,B-L^(x3b)  XVIIIwherein L^(x3b) represents a metal halide (for example a zinc halide(e.g. —ZnCl), or a magnesium halide (e.g. —MgBr)), —Sn(R^(x1))₃, anorganoboronic acid (e.g. an alkyl-cyclotriboroxane derivative or,particularly, —B(OH)₂ or —B(OR^(x1))₂), or an organosilane (e.g.—Si(EtO)₃), in which each R^(x1) is as defined above, and B is asdefined hereinbefore, under reaction conditions known to those skilledin the art, for example such as those described in respect of processstep (ii)(a) above;

-   (viii) for compounds of formula I in which L² represents —NR^(3a)—,    -   (a) reaction of a compound of formula XIX,

wherein X^(4a) represents a suitable leaving group (such as chloro,bromo, iodo or a sulfonate group (e.g. —OS(O)₂CF₃, —OS(O)₂CH₃ or—OS(O)₂PhMe)), and L¹, A, and R¹ are as defined hereinbefore, with acompound of formula XX,B—NHR^(3a)  XXwherein B and R^(3a) are as defined hereinbefore, under reactionconditions known to those skilled in the art, for example such as thosedescribed in respect of process step (iii)(a) above;

-   -   (b) reaction of a compound of formula XXI,

wherein R^(3a), L¹, A, and R¹ are as defined hereinbefore, with acompound of formula XXII,B—X^(4b)  XXIIwherein X^(4b) represents a suitable leaving group (such as chloro,bromo, iodo or a sulfonate group (e.g. —OS(O)₂CF₃, —OS(O)₂CH₃ or—OS(O)₂PhMe)), and B represents Cy² or Het^(B), as defined hereinbefore,except that the Cy² or Het^(B) group contains a fully saturated carbonatom that is attached to X^(4b), under reaction conditions known tothose skilled in the art, for example such as those described in respectof process step (iii)(a) above;

-   -   (c) reaction of a compound of formula XXI as defined above, with        a compound of formula XXIII,        B-L^(x4a)  XXIII        wherein L^(x4a) represents a suitable leaving group, —B(OH)₂ or        —B(OR^(x1))₂ in which each R^(x1) is as defined above, and B is        as defined hereinbefore, except that Cy² or Het^(B) contains an        aromatic ring that is attached to L^(x4a) via a carbon atom,        under reaction conditions known to those skilled in the art, for        example such as those described in respect of process step        (iii)(c) above;    -   (d) reaction of a compound of formula XXIV,

wherein L^(x4b) represents —B(OH)₂ or —B(OR^(x1))₂ in which each R^(x1)is as defined above, and L¹, A, and R¹ are as defined hereinbefore, witha compound of formula XX as defined above, under reaction conditionsknown to those skilled in the art, for example such as those describedin respect of process step (iii)(c) above;

-   (ix) for compounds of formula I in which L² represents —O— or —S—,    -   (a) reaction of a compound of formula XIX as defined above, with        a compound of formula XXV,        B-Q^(c)-H  XXV        wherein Q^(c) represents O or S, and B is as defined        hereinbefore, under reaction conditions known to those skilled        in the art, for example such as those described in respect of        process step (iv)(a) above;    -   (b) reaction of a compound of formula XXVI,

wherein Q^(d) represents O or S, and L¹, A and R¹ are as definedhereinbefore, with a compound of formula XXII as defined above, underreaction conditions known to those skilled in the art, for example suchas those described in respect of process step (iv)(a) above;

-   (x) for compounds of formula I in which L² represents —O— and B    represents Cy² or Het^(B) as defined hereinbefore, except that the    Cy² or Het^(B) group is directly attached to the rest of the    molecule via a fully saturated carbon atom, reaction of a compound    of formula XXV, wherein Q^(c) is O and B is as defined hereinbefore,    with a compound of formula XXVI wherein Q^(d) is O and L¹, A and R¹    are as defined hereinbefore, under reaction conditions known to    those skilled in the art, for example the reaction may be performed    at a suitable temperature (e.g. from room temperature to about 180°    C.), in the presence of a suitable coupling agent (such as a    dialkylazodicarboxylate (e.g. diethylazodicarboxylate) together with    a trialkyl or triaryl phosphine (e.g. PPh₃)), and an appropriate    solvent (e.g. tetrahydrofuran, dimethylsulfoxide, pyridine, toluene,    dichloromethane, chloroform, acetonitrile, dimethylformamide,    trifluoromethylbenzene, dioxane or triethylamine);-   (xi) for compounds of formula I in which L² represents —S(O)— or    —S(O)₂—, oxidation of a compound of formula I in which L² represents    —S— wherein A, L¹, B, and R¹ are as defined hereinbefore, in the    presence of a suitable oxidising agent, under reaction conditions    known to those skilled in the art, for example such as those    described in respect of process step (vi) above;-   (xii) for compounds of formula I in which L¹ and/or L² represents    N(R^(3x)), wherein R^(3x) takes the same definition as R^(3a) above,    except that R^(3x) does not represent H, reaction of a corresponding    compound of formula I in which L¹ and/or L² is NH, with a compound    of formula XXVII,    X^(5a)—R^(3x)  XXVII    wherein X^(5a) represents a suitable leaving group such as one    defined hereinbefore in respect of X^(2a) or —Sn(R^(x1))₃ in which    R^(3x) and each R^(x1) are as defined above, under reaction    conditions known to those skilled in the art, for example in the    case where X^(5a) represents a leaving group (such as iodo, bromo,    chloro or a sulfonate group), the reaction may be performed at a    suitable temperature (e.g. from room temperature to about 180° C.),    optionally in the presence of a suitable base (e.g. sodium hydride,    sodium bicarbonate, potassium carbonate, pyrrolidinopyridine,    pyridine, triethylamine, tributylamine, trimethylamine,    dimethylaminopyridine, diisopropylamine, diisopropylethylamine,    1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide,    N-ethyldiisopropylamine,    N-(methylpolystyrene)-4-(methylamino)pyridine, potassium    bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium    tert-butoxide, lithium diisopropylamide, lithium    2,2,6,6-tetramethylpiperidine or mixtures thereof) and an    appropriate solvent (e.g. tetrahydrofuran, pyridine, toluene,    dichloromethane, chloroform, acetonitrile, dimethylformamide,    trifluoromethylbenzene, dioxane or triethylamine). In the case when    X represents —B(OH)₂ or —Sn(alkyl)₃, the reaction may be performed    in the presence of a suitable catalyst system, (e.g. a metal (or a    salt or complex thereof) such as CuI (or CuI/diamine complex), Cu,    Cu(OAc)₂, copper tris(triphenyl-phosphine)bromide, Pd/C, PdCl₂,    Pd(OAc)₂, Pd(Ph₃P)₂Cl₂, Pd(Ph₃P)₄, Pd₂(dba)₃ or NiCl₂ and a ligand    such as t-Bu₃P, (C₆H₁₁)³P, Ph₃P, AsPh₃, P(o-ToI)₃,    1,2-bis(diphenylphosphino) ethane,    2,2′-bis(di-tert-butylphosphino)-1,1′-bi-phenyl,    2,2′-bis(diphenylphosphino)-1,1′-bi-naphthyl,    1,1′-bis(diphenylphosphinoferrocene),    1,3-bis(diphenylphosphino)-propane, xantphos, or a mixture thereof),    together with a suitable base (such as, Na₂CO₃, K₃PO₄, Cs₂CO₃, NaOH,    KOH, K₂CO₃, CsF, Et₃N, (i-Pr)₂NEt, t-BuONa or t-BuOK, NaH, Et₃N,    pyridine, N,N′-dimethylethylenediamine, (or mixtures thereof,    optionally in the presence of 4 Å molecular sieves)) in a suitable    solvent (such as dioxane, toluene, ethanol, isopropanol, ethylene    glycol, dimethylformamide, ethylene glycol dimethyl ether, water,    dimethylsulfoxide, acetonitrile, dimethylacetamide,    N-methylpyrrolidinone, tetrahydrofuran or mixtures thereof);-   (xiii) reaction of a compound of formula XXVIII,

wherein X⁶ represents a suitable leaving group (such as chloro, bromo,iodo, a sulfonate group (e.g. —OS(O)₂CF₃, —OS(O)₂CH₃ or —OS(O)₂PhMe), asulfone group (e.g. —S(O)₂CH₃, —S(O)₂CF₃ or —S(O)₂-PhMe) or —OR^(4x),wherein R^(4x) represents an aryl or heteroaryl group), and A, B, L¹ andL² are as defined hereinbefore, with a compound of formula XXIX,R¹NH₂  XXIXwherein R¹ is as defined hereinbefore, under reaction conditions knownto those skilled in the art, for example such as those described inrespect of process step (iii)(a) above;

-   (xiv) for compounds of formula I, reaction of a compound of formula    XXX,

wherein R^(x2) represents a suitable leaving group (e.g. a tosyl,mesylate group or an electron deficient aryl or heteroaryl group (suchas pentafluorophenyl)) and A, B, L¹ and L² are as defined hereinbefore,or a protected derivative thereof, with a compound of formula XXIX,wherein R¹ is as defined hereinbefore, under conditions known to thoseskilled in the art, for example the reaction may be performed at aroundroom temperature or above (e.g. up to 40-180° C.), in a suitable solventsuch as dioxane, ethanol, isopropanol, dimethylformamide, acetonitrile,tetrahydrofuran or mixtures thereof;

-   (xv) for compounds of formula I in which both L¹ and L² represent    direct bonds, reaction of a compound of formula XXXI,

wherein A and B are as defined hereinbefore, with a compound of formulaXXXII,

wherein R¹ is as defined hereinbefore, under reaction conditions knownto those skilled in the art, for example as described in WO 92/02513;

-   (xvi) for compounds of formula I in which L¹ represents a direct    bond and A represents a nitrogen-containing Het^(A) group that is    attached via a nitrogen atom within the ring system, reaction of a    compound of formula VII as defined above, with a compound of formula    XXXIII.    Het^(A1)-H  XXXIII    wherein Het^(A1) takes the same definition as Het^(A) as defined    above, except that Het^(A1) is a nitrogen-containing heterocycle    that is attached to the H-atom depicted for the compound of formula    XXXIII via a nitrogen atom in the heterocycle, under reaction    conditions known to those skilled in the art, for example such as    those described in respect of process step (iii)(a) above;-   (xvii) for compounds of formula I in which L² represents a direct    bond and B represents a nitrogen-containing Het^(B) group that is    attached via a nitrogen atom within the ring system, reaction of a    compound of formula XIX as defined above, with a compound of formula    XXXIV,    Het^(B2)-H  XXXIV    wherein Het^(B2) takes the same definition as Het^(B) as defined    above, except that Het^(B2) is a nitrogen-containing heterocycle    that is attached to the H-atom depicted for the compound of formula    XXXIV via a nitrogen atom in the heterocycle, under reaction    conditions known to those skilled in the art, for example such as    those described in respect of process step (iii)(a) above;-   (xviii) for compounds of formula I in which L¹ represents a direct    bond and A represents a phenyl group optionally substituted by one    or more R^(4a) groups, reaction of a compound of formula XXXV,

wherein X⁷ represents a suitable leaving group (such as chloro, bromo,iodo, a sulfonate group (e.g. —OS(O)₂CF₃, —OS(O)₂CH₃ or —OS(O)₂PhMe),and L², B and R^(4a) are as defined hereinbefore, with a compound offormula XXXVI,

wherein R¹ is as defined hereinbefore, under reaction conditions knownto those skilled in the art, for example as described in WO 00/66568;

-   (xix) for compounds of formula I in which L¹ represents —CH═CH—,    reaction of a compound of formula V as defined above, with a    compound of formula XXXVII,    A-CH═CH-L^(x5a)  XXXVII    wherein L^(x5a) represents a metal halide (for example a zinc halide    (e.g. —ZnCl) or a magnesium halide (e.g. —MgBr)), —Sn(R^(x1))₃,    —B(OH)₂, —B(OR^(x1))₂, or an organosilane (e.g. —Si(OEt)₃), wherein    each R^(x1) is as defined above, and A is as defined hereinbefore,    under reaction conditions known to those skilled in the art, for    example such as those described in respect of process step (ii)(a)    above; and-   (xx) for compounds of formula I in which one of R^(4a) to R^(4d)    represents —OH, reaction of a compound of formula I in which one of    R^(4a) to R^(4d) represents —OR^(4y), wherein R^(4y) represents a    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, which    groups are optionally substituted by one or more substituents    selected from halo, C₁₋₄ alkyl and aryl, with an appropriate    dealkylating agent (such as boron tribromide,    2-(diethylamino)ethanethiol or a hydrogen halide (e.g. HBr)), under    reaction conditions known to those skilled in the art, for example    in a suitable solvent (e.g. dichloromethane, dimethylformamide,    dioxane, toluene, ethanol, isopropanol, dimethylsulfoxide,    acetonitrile, dimethylacetamide, tetrahydrofuran or a mixture    thereof, or an ionic liquid (e.g. [bmim][BF₄])), and at a suitable    temperature (e.g. from room temperature to about 180° C.), e.g. as    described in I. Ryu et al., J. Am. Chem. Soc., 2002, 124,    12946-12947; J. Magano et al., J. Org. Chem., 2006, 71, 7103-7105;    or S. K. Boovanahalli et al., J. Org. Chem., 2004, 69, 3340-3344.

Compounds of formula XXVIII wherein X⁶ represents OR^(4x), may beprepared by reaction of a compound of formula XXXVIII.

wherein A, B, L¹ and L² are as defined hereinbefore, with a compound offormula XXXIXa,R^(4x)—OH XXXIXawherein R^(4x) is as described hereinbefore, under reaction conditionsknown to those skilled in the art, for example as described in Frenchpatent no. 2,485,531.

Compounds of formula XXVIII wherein L¹ represents a direct bond and X⁶represents a sulfone group (e.g. —S(O)₂CH₃, —S(O)₂CF₃ or —S(O)₂-PhMe),may be prepared by reaction of a compound of formula XXXIXb,

wherein L^(1aa) represents a halogen atom (such as chloro, bromo or,preferably, iodo), X⁶ represents a sulfone group, and A, B and L² are asdefined hereinbefore, with a compound of formula VI as definedhereinbefore, under reaction conditions known to those skilled in theart, for example such as those described in respect of process step(ii)(a) above).

Compounds of formula XXVIII wherein L² represents a direct bond and X⁶represents a sulfone group (e.g. —S(O)₂CH₃, —S(O)₂CF₃ or —S(O)₂-PhMe),may be prepared by reaction of a compound of formula XXXIXc,

wherein L^(2aa) represents a halogen atom (such as chloro, bromo or,preferably, iodo), X⁶ represents a sulfone group, and A, B and L¹ are asdefined hereinbefore, with a compound of formula XVIII as definedhereinbefore, under reaction conditions known to those skilled in theart, for example such as those described in respect of process step(ii)(a) above).

Other intermediate compounds (e.g. intermediate XXVIII) which containthe 1,2,4-triazine core common to the compounds of formula I, may beprepared by reaction of a compound of formula XXXI as defined above,with a compound of formula XL,

wherein R^(7x) represents a corresponding C₁₋₆ alkyl or aryl group,under reaction conditions known to those skilled in the art, for exampleas described in WO 92/02513, optionally followed by oxidation of thesulfur atom to the desired oxidation state.

Compounds of formula VI wherein L^(x1b) represents B(OH)₂, may beprepared by reaction of a compound of formula XLI,A-H  XLIwherein A is as defined hereinbefore, with a boronic acid derivative(such as bis(pinacolato)diboron, trimethylborate), under reactionconditions known to those skilled in the art, for example in thepresence of an appropriate metal catalyst (or a salt or complex thereof,such as [Ir(COD)(OMe)]₂, [Rh(COD)(OMe)]₂, [Rh(COD)Cl]₂, Cu, Cu(OAc)₇,CuI (or CuI/diamine complex), copper tris(triphenyl-phosphine)bromide,Pd(OAc)₂ or Pd₂(dba)₃) and an optional additive (such as4,4′-di-tert-butyl-2,2′-bipyridine(dtbpy), Ph₃P,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, xantphos, NaI or anappropriate crown ether such as 18-crown-6-benzene), in the presence ofan appropriate base (such as NaH, Et₃N, pyridine,N,N′-dimethylethylenediamine, triethanolamine. N-methyldiethanolamine,N,N-diisopropylethanolamine, triisopropanolamine, Na₂CO₃, K₂CO₃, K₃PO₄.Cs₂CO₃, t-BuONa or t-BuOK or a mixture thereof, optionally in thepresence of 4 Å molecular sieves), in a suitable solvent (e.g.dichloromethane, dimethylformamide, dioxane, toluene, ethanol,isopropanol, dimethylsulfoxide, acetonitrile, dimethylacetamide,tetrahydrofuran or a mixture thereof, or an ionic liquid (e.g.[bmim][BF₄])), and at a suitable temperature (e.g. from room temperatureto about 180° C.), e.g. as described in J. M. Murphy, C. C. Tzschucke,J. F. Hartwig, Org. Lett., 2007, 9, 757-760.

Compounds of formulae IIa, IIb, III, IV, VI, VII, VIII, IX, X, XI, XII,XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV,XXVI, XXVII, XXIX, XXX, XXXI, XXXII, XXXIV, XXXV, XXXVI, XXXVII,XXXVIII, XXXIXa, XXXIXb, XXXIXc, XL and XLI are either commerciallyavailable, are known in the literature, or may be obtained either byanalogy with the processes described herein (or processes described inreferences contained herein), or by conventional synthetic procedures,in accordance with standard techniques, from available startingmaterials using appropriate reagents and reaction conditions.

Substituents, such as R^(3a), R^(4a), R^(4b), R^(4c) and R^(4d) in finalcompounds of formula I (or precursors thereto and other relevantintermediates) may be modified one or more times, after or during theprocesses described above by way of methods that are well known to thoseskilled in the art. Examples of such methods include palladium-mediatedcross couplings or, particularly, substitutions, reductions (e.g.carbonyl bond reductions in the presence of suitable and, if necessary,chemoselective, reducing agents such as LiBH₄ or NaBH₄), oxidations,alkylations, acylations, hydrolyses, esterifications andetherifications. The precursor groups can be changed to a different suchgroup, or to the groups defined in formula I, at any time during thereaction sequence.

Compounds of the invention may be isolated from their reaction mixturesusing conventional techniques (e.g. recrystallisation, columnchromatography, preparative HPLC, etc.).

In the processes described above and hereinafter, the functional groupsof intermediate compounds may need to be protected by protecting groups.

The protection and deprotection of functional groups may take placebefore or after a reaction in the above-mentioned schemes.

Protecting groups may be removed in accordance with techniques that arewell known to those skilled in the art and as described hereinafter. Forexample, protected compounds/intermediates described herein may beconverted chemically to unprotected compounds using standarddeprotection techniques.

The type of chemistry involved will dictate the need, and type, ofprotecting groups as well as the sequence for accomplishing thesynthesis.

The use of protecting groups is fully described in “Protective Groups inOrganic Chemistry”, edited by J W F McOmie, Plenum Press (1973), and“Protective Groups in Organic Synthesis”, 3^(rd) edition, T. W. Greene &P. G. M. Wutz, Wiley-Interscience (1999).

As used herein, the term “functional groups” means, in the case ofunprotected functional groups, hydroxy-, thiolo-, aminofunction,carboxylic acid and, in the case of protected functional groups, loweralkoxy, N-, O-, S-acetyl, carboxylic acid ester.

Some of the intermediates referred to hereinbefore are novel. Accordingto a further aspect of the invention there is thus provided: (a) acompound of formula XXVIII, or a protected derivative thereof, in whichX⁶ represents SO₂R^(x6), wherein R^(x6) represents C₁₋₁₂ alkyloptionally substituted by one or more halo (e.g. fluoro) atoms, orR^(x6) represents phenyl optionally substituted by one or moresubstituents selected from C₁₋₆ alkyl (e.g. methyl), nitro and halo(e.g. bromo); (b) a compound of formula XXXIXb, or a protectedderivative thereof; and (c) a compound of formula XXXIXc, or a protectedderivative thereof.

Biological Tests

The cell lines mentioned below were all purchased from the EuropeanCollection of Cell Cultures (ECACC:http://www.hpacultures.org.uk/collections/ecacc.jsp).

Test A

HEK293-hA_(2a) [³H]-ZM241385/CHO-hA₁ [³H]DPCPX Binding Assay

Test Compounds

All test compounds were prepared as a stock solution of 10 mM in 100%DMSO.

Inhibition binding assays were performed using 2.5 μg of membranesprepared from HEK293 cells transiently transfected with human adenosineA_(2a) receptor or 10 μg of membranes prepared from CHO cells stablytransfected with human adenosine A₁ receptor. Membranes were incubatedin 50 mM Tris-HCl (HEK293-hA_(2a); pH 7.4) or 20 mM HEPES, 100 mM NaCl,10 mM MgCl₂ (CHO-hA₁; pH 7.4) in the presence of varying concentrationsof test compound and 1 nM [³H]ZM241385 (HEK293-hA_(2a)) or [³H]DPCPX(CHO-hA₁) at 25° C. for 1 h. The assay was then terminated by rapidfiltration onto GF/B grade Unifilter plates using a TomTec cellharvester, followed by 5×0.5 ml washes with double distilled H₂O.Nonspecific binding was defined in the presence of 1 μM CGS15943(HEK293-hA_(2a)) or 1 μM DPCPX (CHO-hA₁). Bound radioactivity wasdetermined by liquid scintillation counting (Trilux Microbeta® Counter)and inhibition curves were analysed using a four-parameter logisticequation. IC₅₀ values were converted to K_(i) values with theCheng-Prusoff equation using a K_(D) value derived from saturationbinding studies.

Test B

Catalepsy Reversal Test

The dopamine D₂ receptor antagonist, haloperidol, induces Parkinsonismin humans and induces motor effects in rats such as catalepsy. There isconsiderable evidence that adenosine A_(2A) receptor antagonists reversehaloperidol-induced motor effects in preclinical studies. Suggestedmechanisms by which these effects are mediated include the hypothesisthat A_(2A) receptor antagonism modulates D₂ receptor sensitivity suchthat D₂ receptors exhibit increased sensitivity to striatal dopamine inthe presence of an A_(2A) receptor antagonist. The present studydetermines the ability of haloperidol-induced catalepsy in rats to bereversed by novel A_(2A) receptor antagonists.

Catalepsy was monitored individually in Sprague-Dawley rats (CharlesRiver, UK; 200-250 g; n=8/group) by gently placing each paw in turn on alarge rubber bung. A score of 1 is given for each paw which remains inposition for 15 seconds, giving each rat a maximum score of 4.Haloperidol (0.82 mg/kg, i.p.; 150 min pre-test time) inducessignificant cataleptic behaviour in rats (average score 3.1). The effectof selected compounds of the invention (2-10 mg/kg or 0.3-3 mg/kg, p.o.;120 min pre-test time) on catalepsy was established by administration ofsaid compounds to rats pre-treated with haloperidol as described above.

Details of a similar test may be found in, for example, Hodgson et al.,J. Pharmacol. Exp. Ther. 330, 2009, 294-303.

EXAMPLES

Where no preparative routes are included, the relevant intermediate iscommercially available (e.g. from Sigma Aldrich or Manchester OrganicsLtd).

General Procedures

Commercial reagents were utilized without further purification. Roomtemperature refers to 20-27° C. Melting points, wherever reported, areuncorrected. ¹H-NMR spectra were recorded at 400 MHz on a Brukerinstrument. Chemical shift values are expressed in parts per million,i.e. (δ)-values. The following abbreviations are used for themultiplicity for the NMR signals: s=singlet, b=broad, d=doublet,t=triplet, q=quartet, qui=quintet, h=heptet, dd=doublet of doublets,dt=double of triplets, m=multiplet Coupling constants are listed as Jvalues, measured in Hz. NMR and mass spectroscopy results were correctedto account for background peaks. Chromatography refers to columnchromatography performed using 60-120 mesh silica gel and executed undernitrogen pressure (flash chromatography) conditions. The TLC formonitoring the reaction means the TLC run using the specified mobilephase and the Silica gel F254 as a stationary phase from Merck.Microwave-mediated reactions were performed in a Biotage Initiator.

HPLC purities were measured under the following conditions:

Instrument: Waters Alliance 2695. Column: Sunfire C-18, 250×4.6 mm, 5μm, or equivalent. Gradient [time (min)/% solvent B in A]: 0.00/10,9.00/90, 11.00/100, 20.00/100, 20.01/10, 25.00/10 (solvent A=0.1% formicacid in water; solvent B=0.1% formic acid in acetonitrile), 1 mL/min;detection wavelength specified for each compound in the detailedexperimental section.

Mass spectroscopy was carried out on a Shimadzu LCMS-2010 EV, usingelectrospray conditions as specified for each compound in the detailedexperimental section.

LCMS experiments were carried out with methods A-C, as specified foreach compound in the detailed experimental section, using the followingconditions:

LCMS method A: Instruments: Waters Alliance 2795, Waters 2996 PDAdetector, Micromass ZQ. Column: Waters X-Bridge C-18, 2.5 micron, 2.1×20mm or Phenomenex Gemini-NX C-18, 3 micron, 2.0×30 mm. Gradient [time(min)/solvent D in C (%)]: 0.00/2, 0.10/2, 2.50/95, 3.50/95, 3.55/2,4.00/2 (solvent C=1.58 g ammonium formate in 2.5 L water+2.7 mL ammoniasolution; solvent D=2.5 L Acetonitrile+132 mL (5%) solvent C+2.7 mLammonia solution). Injection volume 5 uL; UV detection 230 to 400 nM;column temperature 45° C.

LCMS method B: Instrument: Waters Semi-Prep LCMS with ZQ MS. Column:Agilent Prep-C18 Scalar, 5 μm, 4.6×50 mm Detection wavelength: 254 nmand 215 nm. Gradient [time (min)/solvent B in A (%), flow rate]: 0.00/5(2.5 mL/min), 0.10/5 (2.5 mL/min), 5.0/95 (2.5 mL/min), 5.50/95 (2.5mL/min), 5.60/95 (3.5 mL/min), 6.60/95 (3.5 mL/min), 6.75/5 (3.5 mL/min)6.90/5 (3.5 mL/min), 7.00/5 (2.5 mL/min), (solvent A: water with 0.1%NH₄OH; solvent B: MeOH with 0.1% NH₄OH).

LCMS method C: Instruments: Waters Alliance 2795. Waters 2996 PDAdetector, Micromass ZQ. Column: Waters X-Bridge C-18, 2.5 micron, 2.1×20mm or Phenomenex Gemini-NX C-18, 3 micron, 2.0×30 mm. Gradient [time(min)/solvent D in C (%)]: 0.00/2, 0.10/2, 8.40/95, 9.40/95, 9.50/2,10.00/2 (solvent C=1.58 g ammonium formate in 2.5 L water+2.7 mL ammoniasolution; solvent D=2.5 L Acetonitrile+132 mL (5%) solvent C+2.7 mLammonia solution). Injection volume 5 uL; UV detection 230 to 400 nM;column temperature 45° C.: 1.5 mL/min.

Preparative HPLC was typically carried out with instrument A or B usingan acidic method (gradients of acetonitrile and water, each containing0.1% formic acid) or a basic method (gradients of methanol and water,each containing 0.1% NH₄OH) Instrument A conditions: Waters delta 600HPLC. Column: X-bridge C-18, 250×19 mm, 5 μm, or equivalent Flow rate:19 mL/min.

Instrument B: Gilson HPLC. Column: Agilent Zorbax Extend Cartridge, 5μm, 21.2×100 mm. Guard Column: Agilent Prep-C18 Guard Cartridge, 10 μm.Flow rate: 28 mL/min.

Preparation 1

Procedure for the Preparation of Methyl Hydrazinecarbimidothioate

Methyl hydrazinecarbimidothioate was prepared by drop wise addition ofmethyl iodide (2.80 g, 19.8 mmol) to a solution of thiosemicarbazide(1.80 g, 19.75 mmol) in ethanol (50 mL). The resulting mixture wasrefluxed for 2.5 hrs with TLC monitoring (methanol/DCM, 1:9). Thereaction mixture was then concentrated in vacuo and the crude compound(1.80 g, 90%) was used in the next step without any furtherpurification.

Mass spectroscopy: (ESI+ve) 106 [M−H]⁺

Typical Procedure for the Preparation of Arylglyoxal Derivatives, asExemplified with (i) 4-fluorophenylglyoxal

Selenium dioxide (6.70 g, 61.0 mmol) was added to a solution of4-fluoroacetophenone (8.43 g, 61.0 mmol) in dioxane (100 mL) and water(3 mL), and the resulting mixture was heated at 55° C. until completedissolution of selenium dioxide had occurred. The reaction mass was thenrefluxed for 5-6 hrs. After completion of the reaction (TLC), themixture was filtered and the filtrate was concentrated in vacuoaffording a viscous oil. Water (50 mL) was added and the resultingmixture was stirred for 12 hrs, after which time the solid was collectedon a filter, washed with water (25 mL) and dried in vacuo, affording4-fluorophenylglyoxal (6.60 g, 85%).

¹H NMR: (400 MHz, CDCl₃) δ: 7.18 (m, 2H), 8.11 (d, 2H), aldehyde CHOsignal not observed.

(ii) (3-Chloro-5-fluorophenyl)(oxo)acetaldehyde

(3-Chloro-5-fluorophenyl)(oxo)acetaldehyde (27 g, 84%) was prepared from3-chloro-5-fluoro acetophenone (30.0 g, 174.4 mmol) and selenium dioxide(21.28 g, 191.8 mmol) according to the typical procedure used forPreparation 1.

(iii) (3,5-Difluorophenyl)(oxo)acetaldehyde

(3,5-Difluorophenyl)(oxo)acetaldehyde (28 g, 84%) was prepared from3,5-difluoro acetophenone (30.0 g, 192.3 mmol) and selenium dioxide(23.55 g, 214.0 mmol) according to the typical procedure used forPreparation 1.

(iv) 4-(Methoxymethyl)phenylglyoxal Step 1: Preparation of4-(Methoxymethyl)benzonitrile

4-(Hydroxymethyl) benzonitrile (6.0 g, 45.09 mmol) was dissolved in THF(60 mL), cooled to −5° C. to −10° C. and treated with sodium hydride(2.16 g, 90.19 mmol). The resulting mixture was stirred for 30 minutesthen treated with methyl iodide (9.6 g, 67.65 mmol) at RT for 2 hours.After completion of the reaction (TLC: ethyl acetate/Hexane, 5:5), themixture was poured into water (50 mL) and extracted with ethyl acetate(3×25 mL). The separated organic layers were combined, dried over Na₂SO₄and concentrated in vacuo. The crude compound was purified by gradientflash chromatography, eluting with 5% ethyl acetate in hexane to afford4-(methoxymethyl)benzonitrile (6.7 g, 90%).

HPLC purity: 99.20% (232 nm)

Mass spectroscopy: (ESI+ve) 148.0 [M+H]⁺.

Step 2: Preparation of 1-[4-(methoxymethyl)phenyl]ethanone

4-(Methoxymethyl)benzonitrile (6.0 g, 40.82 mmol) was dissolved inTHF/diethyl ether (1:1, 60 mL) and the resulting solution was cooled to−10° C. 3 M solution of methyl magnesium iodide (13.57 g, 81.63 mmol)was added and the resulting mixture was stirred at this temperature for5 hours. After completion of the reaction (TLC; toluene/methanol, 97:3),the mixture was poured into acidified water (50 mL; pH 3-4) andextracted with ethyl acetate (3×50 mL). The separated organic layerswere combined, dried over Na₂SO₄ and concentrated in vacuo. The crudecompound was purified by gradient flash chromatography, eluting with 8%ethyl acetate in hexane to afford the target compound (3.7 g, 55%).

Mass spectroscopy: (ESI+ve) 165.0 [M+H]⁺.

Step 3: Preparation of 4-(methoxymethyl)phenylglyoxal

Selenium dioxide (3.53 g, 31.84 mmol) was dissolved in 1,4-dioxane (50mL) and water (0.5 mL). The solution was warmed to 40° C. and treatedwith 1-(4-(methoxymethyl)phenyl)ethanone (3.9 g, 26.53 mmol); theresulting mixture was refluxed for 6 hours and monitored by TLC(chloroform/methanol, 95:5). After completion of the reaction, themixture was filtered through celite and concentrated in vacuo. The crudecompound was purified by column chromatography eluting with up to 15%ethyl acetate in hexane, affording the target glyoxal (4.0 g, 85%).

Mass spectroscopy: (ESI+ve) 179.0[M−H]⁻

(v) 2-Pyrimidineglyoxal Step 1: Preparation of1-(pyrimidin-2-yl)ethanone

A solution of 2-cyano-pyrimidine (10.0 g, 95.2 mmol) in THF (100 mL) wascooled to −5° C. and treated with a 3 M solution of methyl magnesiumbromide in THF (38.0 mL, 98.4 mmol). The reaction was stirred at 0° C.for two hours until completion was observed by TLC (chloroform/methanol,9:1). The reaction mixture was poured in water; the pH was adjusted to5-6 and the aqueous layer was extracted with ethyl acetate (3×150 mL).The combined organic layers were concentrated under reduced pressure andthe crude compound was purified by column chromatography, eluting withchloroform to afford the target compound (6.5 g, 48%).

HPLC purity: 97.2% (223 nm).

Mass spectroscopy: (ESI+ve) 123.1 [M+H]⁺

Step 2: Preparation of 2-pyrimidineglyoxal

A solution of selenium dioxide (15 g, 135 mmol) in ethanol (150 mL) wasstirred at 50° C. until a clear solution was obtained,1-(Pyrimidin-2-yl)ethanone (10 g, 82.0 mmol) was added to the resultingmixture which was stirred for 6 hrs at 78° C. with TLC monitoring. Thiscrude mixture was then used in next step without further purification.

Mass spectroscopy: (ESI+ve) 137.1 [M+H]⁺

TLC R_(f): 0.3 (chloroform/methanol, 9:1)

(vi) 2-Pyridylglyoxal

2-Pyridylglyoxal (8.0 g, crude) was prepared from selenium dioxide (15g, 135 mmol) and 2-acetyl pyridine (10 g, 82 mmol) according to thetypical procedure used for Preparation 1.

TLC R_(f): 0.1 (ethyl acetate)

Mass spectroscopy: (ESI+ve) 136.1 [M+H].

(vii) 3-pyridyiglyoxal

3-Pyridylglyoxal (5.0 g, crude) was prepared from selenium dioxide (6.82g, 61.4 mmol) and 3-acetyl pyridine (5.0 g, 41.0 mmol) according to thetypical procedure used for Preparation 1.

Mass spectroscopy: (ESI+ve) 136.1 [M+H]⁺.

TLC R_(f): 0.1 (ethyl acetate)

Phenylglyoxal monohydrate is commercially available from Sigma Aldrich.2,4-difluorophenylglyoxal and 3-methoxyphenylglyoxal are commerciallyavailable from Manchester Organics Ltd.

Preparation 2

General Procedure for the Preparation of 5-Aryl-1,2,4-Triazin-3-AmineDerivatives from Arylglyoxal Derivatives

Step 1: A solution of an arylglyoxal derivative (19.7 mmol) in ethanol(50 mL) is treated successively with sodium bicarbonate (3.32 g, 39.5mol) and methyl hydrazinecarbimidothioate (19.7 mmol) and the resultingmixture is refluxed for 3 hrs. After completion of the reaction (TLC),the mixture is concentrated in vacuo, poured into water (50 mL), andextracted with DCM or ethyl acetate (2×25 mL). The combined organicextracts are then dried over Na₂SO₄, concentrated in vacuo, and purifiedby gradient flash chromatography, affording intermediate A, a3-(methylsulfanyl)-5-aryl-1,2,4-triazine derivative.

Step 2: m-CPBA (7.44 g, 43.3 mmol) is added to a solution ofintermediate A (14.4 mmol) in DCM (50 mL) at −20 to −15° C. and theresulting mixture is stirred at this temperature until the reaction isjudged to be complete by TLC (typically 8 hrs). The reaction is thenquenched with saturated aqueous NaHCO₃ solution (100 mL) and extractedwith ethyl acetate (2×25 mL). The combined organic extracts are driedover Na₂SO₄ and evaporated under reduced pressure. The crude product,intermediate B, a 3-(methylsulfonyl)-5-aryl-1,2,4-triazine derivative,is purified by gradient flash chromatography.

Step 3: 0.5 M ammonia in THF (100 mL, 500 mmol) is cooled to −33° C. andtreated with ferric nitrate (5.50 g, 13.6 mmol) for 10 minutes. Asolution of intermediate B (13.6 mmol) in THF (15 mL) is then introducedby drop wise addition and the mixture is stirred for 4 hrs withmonitoring by TLC (methanol/DCM, 1:9). After completion of the reaction,the mixture is poured into water (150 mL) and extracted with DCM orethyl acetate (2×50 mL). The combined organic extracts are then driedover Na₂SO₄, concentrated in vacuo and treated with 4N aqueous HClsolution (40-50 mL) for 10 minutes. The aqueous phase is then extractedwith ethyl acetate (150 mL), neutralized with aqueous K₂CO₃ solution(90-100 mL), and re-extracted with ethyl acetate (100 mL). All of theorganic extracts are then combined, dried over Na₂SO₄ and concentratedin vacuo, affording intermediate C, a 5-aryl-1,2,4-triazin-3-aminederivative.

(i) 5-Phenyl-1,2,4-triazin-3-amine

Step 1: 3-(Methylsulfanyl)-5-phenyl-1,2,4-triazine (2.93 g, 73%) wasprepared from methyl hydrazinecarbimidothioate (2.07 g, 19.7 mmol) andphenylglyoxal monohydrate (2.89 g, 19.7 mmol) according to the generalprocedure of Preparation 2.

Mass spectroscopy: (ESI+ve) 204 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 2.73 (s, 3H), 7.53-7.60 (m, 3H), 8.14-8.17(m, 2H), 9.38 (s, 1H).

Step 2: 3-(Methylsulfonyl)-5-phenyl-1,2,4-triazine (3.20 g, 96%) wasprepared from 3-(methylsulfanyl)-5-phenyl-1,2,4-triazine (2.93 g, 14.4mmol) and m-CPBA (7.44 g, 43.3 mmol) according to the general procedureof Preparation 2.

Mass spectroscopy: (ESI+ve) 236.9 [M+H]⁺

Step 3: 5-Phenyl-1,2,4-triazin-3-amine (1.70 g, 73%) was prepared from3-(methylsulfonyl)-5-phenyl-1,2,4-triazine (3.20 g, 13.6 mmol) and 0.5 Mammonia in THF (100 mL, 500 mmol) according to the general procedure ofPreparation 2.

Mass spectroscopy: (ESI+ve) 172.9 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 7.30 (br s, 2H), 7.53-7.60 (m, 3H),8.19-8.21 (dd, 2H), 9.20 (s, 1H).

(ii) 5-(2,4-Difluorophenyl)-1,2,4-triazin-3-amine

Step 1: 3-(Methylsulfanyl)-5-(2,4-difluorophenyl)-1,2,4-triazine (1.00g, 78%) was prepared from methyl hydrazinecarbimidothioate (0.63 g, 6.0mmol) and 2,4-difluorophenylglyoxal monohydrate (1.00 g, 6.0 mmol)according to the general procedure of Preparation 2.

Mass spectroscopy: (ESI+ve) 239.9 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 2.69 (s, 3H), 6.96-7.02 (m, 1H), 7.06-7.11(m, 1H), 8.27-8.33 (m, 1H), 9.46 (s, 1H).

Step 2: 3-(Methylsulfonyl)-5-(2,4-difluorophenyl)-1,2,4-triazine (1.1 g,97%) was prepared from3-(methylsulfanyl)-5-(2,4-difluorophenyl)-1,2,4-triazine (1.00 g, 4.17mmol) and m-CPBA (2.16 g, 4.17 mmol) according to the general procedureof Preparation 2.

Mass spectroscopy: (ESI+ve) 271.9 [M+H]⁺

Step 3: 5-(2,4-Difluorophenyl)-1,2,4-triazin-3-amine (0.45 g, 53%) wasprepared from 3-(methylsulfonyl)-5-(2,4-difluorophenyl)-1,2,4-triazine(1.10 g, 4.05 mmol) and 0.5 M ammonia in THF (50 mL, 25 mmol) accordingto the general procedure of Preparation 2.

Mass spectroscopy: (ESI+ve) 208.9 [M+H]⁺

(iii) 5-(3-Methoxyphenyl)-1,2,4-triazin-3-amine

Step 1: 3-(Methylsulfanyl)-5-(3-methoxyphenyl)-1,2,4-triazine (1.01 g,79%) was prepared from methyl hydrazinecarbimidothioate (0.58 g, 5.50mmol) and 3-methoxyphenylglyoxal monohydrate (1.00 g, 5.50 mmol)according to the general procedure of Preparation 2.

Mass spectroscopy: (ESI+ve) 233.9 [M+H]⁺

Step 2: 3-(Methylsulfonyl)-5-(3-methoxyphenyl)-1,2,4-triazine (0.90 g,79%) was prepared from3-(methylsulfanyl)-5-(3-methoxyphenyl)-1,2,4-triazine (1.00 g, 4.20mmol) and m-CPBA (2.30 g, 12.8 mmol) according to the general procedureof Preparation 2.

Mass spectroscopy: (ESI+ve) 265.9 [M+H]⁺

Step 3: 5-(3-Methoxyphenyl)-1,2,4-triazin-3-amine (0.31 g, 45%) wasprepared from 3-(methylsulfonyl)-5-(3-methoxyphenyl)-1,2,4-triazine(0.90 g, 3.39 mmol) and 0.5 M ammonia in THF (50 mL, 25.0 mmol)according to the general procedure of Preparation 2.

Mass spectroscopy: (ESI+ve) 202.9 [M+H]⁺

(iv) 5-(4-Fluorophenyl)-1,2,4-triazin-3-amine

Step 1: 3-(Methylsulfanyl)-5-(4-fluorophenyl)-1,2,4-triazine (6.00 g,69%) was prepared from methyl hydrazinecarbimidothioate (4.51 g, 43.0mmol) and 4-fluorophenylglyoxal monohydrate (6.60 g, 43.0 mmol)according to the general procedure of Preparation 2.

Mass spectroscopy: (ESI+ve) 221.9 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 2.73 (s, 3H), 7.24 (d, 2H), 8.18 (d, 2H),9.34 (s, 1H).

Step 2: 3-(Methylsulfonyl)-5-(4-fluorophenyl)-1,2,4-triazine (5.00 g,72%) was prepared from3-(methylsulfanyl)-5-(4-fluorophenyl)-1,2,4-triazine (6.00 g, 27.0 mmol)and m-CPBA (12.4 g, 81.0 mmol) according to the general procedure ofPreparation 2.

Mass spectroscopy: (ESI+ve) 253.9 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 3.55 (s, 3H), 7.34 (d, 2H), 8.33 (d, 2H),9.82 (s, 1H).

Step 3: 5-(4-Fluorophenyl)-1,2,4-triazin-3-amine (2.80 g, 74%) wasprepared from 3-(methylsulfonyl)-5-(4-fluorophenyl)-1,2,4-triazine (5.00g, 19.7 mmol) and 0.5 M ammonia in THF (100 mL, 50.0 mmol) according tothe general procedure of Preparation 2.

Mass spectroscopy: (ESI+ve) 191.0[M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 6.79 (s, 2H), 7.40 (m, 2H), 8.23 (m, 2H),9.21 (s, 1H).

(v) 5-[4-(methoxymethyl)phenyl]-1,2,4-triazin-3-amine

Step 1: 5-[4-(methoxymethyl)phenyl]-3-(methylsulfanyl)-1,2,4-triazine(4.0 g, 72%) was prepared from methyl hydrazinecarbimidothioate (7.33 g,31.46 mmol) and 4-(methoxymethyl)phenylglyoxal (4 g, 22.47 mmol)according to the general procedure of Preparation 2.

Mass spectroscopy: (ESI+ve) 248.0 [M−H]⁺

Step 2: 5-[4-(methoxymethyl)phenyl]-3-(methylsulfonyl)-1,2,4-triazine(3.5 g, 83%) was prepared from5-[4-(methoxymethyl)phenyl]-3-(methylsulfanyl)-1,2,4-triazine (3.75 g,15.2 mmol) and m-CPBA (7.92 g, 45.6 mmol) according to the generalprocedure of Preparation 2.

Mass spectroscopy: (ESI+ve) 279.9 [M−H]⁺

Step 3: 5-[4-(methoxymethyl)phenyl]-1,2,4-triazin-3-amine (2.2 g, 85%)was prepared from5-[4-(methoxymethyl)phenyl]-3-(methylsulfonyl)-1,2,4-triazine (3.40 g,12.2 mmol) in THF (35 mL) and treated with NH₃ gas by purging for 30minutes, similarly to the general procedure of Preparation 2.

Mass spectroscopy: (ESI+ve) 217.0 [M+H]⁺.

¹H NMR: (400 MHz, DMSO) δ: 3.32 (s, 3H), 4.48 (s, 2H), 7.22 (s, 2H),7.47 (d, 2H), 8.14 (d, 2H), 9.2 (s, 1H).

(vi) 5-(3-chloro-5-fluorophenyl)-1,2,4-triazin-3-amine

Step 1: 3-(methylsulfanyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine(16 g, 38.4%) was prepared from methyl hydrazinecarbimidothioate (25.5g, 243 mmol) and 2-(3-chloro-5-fluorophenyl)-2-oxoacetaldehyde (30 g,162 mmol) according to the general procedure of Preparation 2.

Mass spectroscopy: (ESI+ve) 255.9 [M−H]⁺

Step 2: 3-(methylsulfonyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine(16 g, 88%) was prepared from3-(methylsulfanyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine (16 g,62.7 mmol) and m-CPBA (16.18 g, 94.11 mmol) according to the generalprocedure of Preparation 2.

Mass spectroscopy: (ESI+ve) 287.9 [M−H]⁺

Step 3: 5-(3-chloro-5-fluorophenyl)-1,2,4-triazin-3-amine (1.70 g, 73%)was prepared from3-(methylsulfonyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine (16.0 g,55.5 mmol) and ammonia gas according to the general procedure ofPreparation 2.

Mass spectroscopy: (ESI+ve) 224.9 [M−H]⁺

(vii) 5-(3,5-difluorophenyl)-1,2,4-triazin-3-amine

Step-1: 3-(methylsulfanyl)-5-(3,5-difluorophenyl)-1,2,4-triazine (28 g,80.0%) was prepared from methyl hydrazine carbimidothioate (20.68 g,197.4 mmol) and 2-(3,5-difluorophenyl)-2-oxoacetaldehyde (25 g, 147.0mmol) according to the general procedure of Preparation 2.

Mass spectroscopy: (ESI+ve) 240.0 [M−H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 2.74 (s, 3H), 7.02-7.07 (m, 1H), 7.69 (d,2H), 9.32 (s, 1H).

Step-2: 3-(methylsulfonyl)-5-(3,5-difluorophenyl)-1,2,4-triazine (31 g,97.7%) was prepared from3-(methylsulfanyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine (28.0 g,117.0 mmol) and m-chloro perbenzoic acid (40 g, 234 mmol) according tothe general procedure of Preparation 2.

Mass spectroscopy: (ESI+ve) 271.9 [M−H]⁺

Step-3: 5-(3,5-difluorophenyl)-1,2,4-triazin-3-amine (18 g, 74%) wasprepared from 3-(methylsulfonyl)-5-(3,5-difluorophenyl)-1,2,4-triazine(31.0 g, 115.0 mmol) and ammonia gas according to the general procedureof Preparation 2.

Mass spectroscopy: (ESI+ve) 209.0 [M+H]⁺.

¹H NMR: (400 MHz, DMSO) δ: 7.37 (bs, 2H), 7.4 (m, 3H), 9.29 (s, 1H).

(viii) 5-(Pyrimidin-2-yl)-1,2,4-triazin-3-amine

Step 1: 3-(Methylsulfanyl)-5-(pyrimidin-2-yl)-1,2,4-triazine (5.0 g,67%) was prepared from methylhydrazinecarbimidothioate (4.8 g 44.1 mmol)and 2-pyrimidineglyoxal (5.0 g, 37 mmol) according to the generalprocedure of Preparation 2.

Mass spectroscopy: (ES+I+ve) 206.0 [M+H]⁺.

Step 2: 3-(Methylsulfonyl)-5-(pyrimidin-2-yl)-1,2,4-triazine (5.0 g,crude) was prepared from3-(methylsulfanyl)-5-(pyrimidin-2-yl)-1,2,4-triazine (5.0 g, 24.3 mmol)and m-CPBA (10.5 g, 58.0 mmol) according to the general procedure ofPreparation 2, without chromatographic purification.

Mass spectroscopy: (ESI+ve) 237.0 [M+H]⁺.

TLC R_(f): 0.5 (chloroform/methanol, 9:1)

Step 3: 5-(Pyrimidin-2-yl)-1,2,4-triazin-3-amine (1.0 g, 23%) wasprepared from 3-(methylsulfonyl)-5-(pyrimidin-2-yl)-1,2,4-triazine (5.0g. crude) and 0.5 M ammonia in THF (20 mL) according to the generalprocedure of Preparation 2.

Mass spectroscopy: (ESI+ve) 175 [M+H]⁺.

The following triazine intermediates were prepared from arylglyoxalderivatives in one step by condensation with aminoguanidine:

(ix) 5-(Pyridin-2-yl)-1,2,4-triazin-3-amine (1.5 g, 8% over 2 steps) wasprepared from a crude sample of 2-pyridylglyoxal (8.0 g) andaminoguanidine hydrogen carbonate (6.0 g, 44 mmol). The reagents wererefluxed in EtOH (100 mL) for 4 hours. The reaction mixture was thencooled, concentrated under reduced pressure and purified by gradientflash chromatography (eluting with 0-30% ethyl acetate/hexane). Thesample contained a mixture of isomers at this stage and was used withoutfurther purification.

HPLC purity: 35%, (265 nm)

Mass spectroscopy: (ESI+ve) 174 [M+H]⁺.

(x) 5-(Pyridin-3-yl)-1,2,4-triazin-3-amine (1.5 g, 16% over 2 steps) wasprepared from a crude sample of 3-pyridylglyoxal (10.0 g) andaminoguanidine hydrogen carbonate (3.0 g, 22 mmol). The reagents wererefluxed in EtOH (100 mL) for 4 hours. The reaction mixture was thencooled, concentrated under reduced pressure and purified by gradientflash chromatography (eluting with 0-30% ethyl acetate/hexane).

Mass spectroscopy: (ESI+ve) 174 [M+H]⁺

TLC R_(f)=0.2 (ethyl acetate)

The following 3-amino-5-aryl-1,2,4-triazine compounds are commerciallyavailable from UkrOrgSynth:

-   5-[4-(difluoromethoxy)phenyl]-1,2,4-triazin-3-amine;-   5-(3-chloro-4-fluorophenyl)-1,2,4-triazin-3-amine;-   5-(3-chlorophenyl)-1,2,4-triazin-3-amine;-   5-(4-chlorophenyl)-1,2,4-triazin-3-amine;-   5-(3,4-difluorophenyl)-1,2,4-triazin-3-amine;-   5-(3-fluorophenyl)-1,2,4-triazin-3-amine;-   4-(3-amino-1,2,4-triazin-5-yl)benzonitrile;-   5-(4-ethylphenyl)-1,2,4-triazin-3-amine;-   5-(4-methylphenyl)-1,2,4-triazin-3-amine;-   5-(2-fluorophenyl)-1,2,4-triazin-3-amine;-   5-(4-methoxyphenyl)-1,2,4-triazin-3-amine and-   5-(2,5-difluorophenyl)-1,2,4-triazin-3-amine.    Preparation 3

General Procedure for the Halogenation of 5-Aryl-1,2,4-Triazin-3-AmineDerivativesMethod 1

A solution of intermediate C, a 5-aryl-1,2,4-triazin-3-amine derivative(8.70 mmol) in DMF (15 mL) is cooled to −25° C. and treated with asolution of N-chlorosuccinimide or N-bromosuccinimide (26.6 mmol) in DMF(10 mL) by drop wise addition. The reaction is stirred overnight andmonitored by TLC (methanol/DCM, 1:9). After completion of the reaction,the mixture is poured into saturated bicarbonate solution (50 mL) andextracted with diethyl ether (25×3 mL). The organic phases are combined,dried over Na₂SO₄ and concentrated in vacuo. The crude compound ispurified by gradient flash chromatography, eluting with mixtures ofethyl acetate in hexane (e.g. 10% ethyl acetate in hexane) to afford thetarget compound, intermediate D.

Method 2

A solution of intermediate C, a 5-aryl-1,2,4-triazin-3-amine derivative(8.70 mmol) in DMF (15 mL) is cooled to −25° C. and treated with asolution of N-chlorosuccinimide or N-bromosuccinimide (26.6 mmol) in DMF(10 mL) by drop wise addition. The reaction is stirred at roomtemperature and monitored by TLC or LCMS. After completion of thereaction, the mixture is poured into saturated bicarbonate solution (50mL) and extracted with an organic solvent such as diethyl ether or ethylacetate. The organic phases are combined, dried over Na₂SO₄ andconcentrated in vacuo. The crude compound is purified by gradient flashchromatography, eluting with mixtures of ethyl acetate in hexane, ormethanol in DCM, to afford the target compound, intermediate D.

(i) 6-Bromo-5-phenyl-1,2,4-triazin-3-amine

6-Bromo-5-phenyl-1,2,4-triazin-3-amine (1.40 g, 64%) was prepared from5-phenyl-1,2,4-triazin-3-amine (1.50 g, 8.70 mmol) andN-bromosuccinimide (4.50 g, 26.6 mmol) according to the generalprocedure of Preparation 3.

Mass spectroscopy: (ESI+ve) 251.9 [M+H]⁺

¹H NMR: (400 MHz, CDCl₁) δ: 5.49 (s, 2H), 7.49-7.58 (m, 3H), 7.82-7.85(m, 2H).

(ii) 6-Chloro-5-phenyl-1,2,4-triazin-3-amine

6-Chloro-5-phenyl-1,2,4-triazin-3-amine (0.38 g, 65%) was prepared from5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) andN-chlorosuccinimide (0.50 g, 3.7 mmol) according to the generalprocedure of Preparation 3.

Mass spectroscopy: (ESI+ve) 207.9 [M+H]⁺

(iii) 6-Bromo-5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine

6-Brom-5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine (0.13 g, 21%) wasprepared from 5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine (0.45 g, 2.1mmol) and N-bromosuccinimide (0.49 g, 2.80 mmol) according to thegeneral procedure of Preparation 3.

Mass spectroscopy: (ESI+ve) 286.8 [M+H]⁺

(iv) 6-Bromo-5-(3-methoxyphenyl)-1,2,4-triazin-3-amine

6-Bromo-5-(3-methoxyphenyl)-1,2,4-triazin-3-amine (0.18 g, 42%) wasprepared from 5-(3-methoxyphenyl)-1,2,4-triazin-3-amine (0.31 g, 1.50mmol) and N-bromosuccinimide (0.35 g, 1.99 mmol) according to thegeneral procedure of Preparation 3.

Mass spectroscopy: (ESI+ve) 280.9 [M+H]⁺

(v) 6-Bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine

6-Bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (1.95 g, 49%) wasprepared from 5-(4-fluorophenyl)-1,2,4-triazin-3-amine (2.8 g, 14.00mmol) and N-bromosuccinimide (7.87 g, 44.00 mmol) according to thegeneral procedure of Preparation 3.

Mass spectroscopy: (ESI+ve) 268.9 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 5.43 (s, 2H), 7.19 (d, 2H), 7.87 (d, 2H).

The following intermediate compounds were also prepared according to thegeneral procedure of Preparation 3:

No. Product (yield) Prepared From LCMS NMR (vi) 6-bromo-5-(3,4- 5-(3,4-Mass spectroscopy: (400 MHz, DMSO) δ: difluorophenyl)-difluorophenyl)-1,2,4- m/z 287, 289 (M + H)⁺ 7.58-7.66 (m, 3H),1,2,4-triazin-3-amine triazin-3-amine (2.8 g, (ES⁺); 285, 287 (M − H)⁻7.77-7.98 (m, 2H). (1.71 g, 44%) 13.45 mmol) (ES⁻), at 4.07 min, 100%(method B). (vii) 6-bromo-5-(3- 5-(3-fluorophenyl)- Mass spectroscopy:(400 MHz, DMSO) δ: fluorophenyl)-1,2,4- 1,2,4-triazin-3-amine m/z (Br)269.6/271.7 7.38-7.47 (m, 1H), triazin-3-amine (1.27 (2.00 g, 10.52mmol) (M + H)⁺ (ES⁺); 7.51-7.70 (m, 5H). g, 44.9%) 267.9/269.9 (M − H)⁻(ES⁻), at 3.85 min, 100% (method B). (viii) 6-bromo-5-(3-5-(3-chlorophenyl)- Mass spectroscopy: (400 MHz, DMSO) δ:chlorophenyl)-1,2,4- 1,2,4-triazin-3-amine m/z (Br, Cl) 7.52-7.66 (m,4H), triazin-3-amine (1.1 (2.00 g, 9.68 mmol) 285.7/287.7/289.77.69-7.73 (m, 1H), g, 40%) (M + H)⁺ (ES⁺); 7.79 (t, J 1.7 Hz, 1H).283.9/285.9/288.0 (M − H)⁻ (ES⁻), at 4.32 min, 100% (method B). (ix)4-(3-amino-6-bromo- 4-(3-amino-1,2,4- Mass spectroscopy: (400 MHz, DMSO)δ: 1,2,4-triazin-5- triazin-5- m/z (Br) 276.6/278.6 7.66 (s, 2H), 7.86-yl)benzonitrile (605 yl)benzonitrile (2.00 (M + H)⁺ (ES⁺); 7.94 (m, 2H),7.99- mg, 21%) g, 10.14 mmol) 274.9/276.9 (M − H)⁻ 8.06 (m, 2H). (ES⁻),at 3.42 min, 98.6% (method B). (x) 6-bromo-5-(4- 5-(4-chlorophenyl)-Mass spectroscopy: (400 MHz, DMSO) δ: chlorophenyl)-1,2,4-1,2,4-triazin-3-amine m/z (Br, Cl) 7.58 (s, 2H), 7.60- triazin-3-amine(890 (2.00 g, 9.68 mmol) 285.0/287.0/289.0 7.65 (m, 2H), 7.74- mg, 32%)(M + H)⁺ (ES⁺); 7.81 (m, 2H). 283.2/285.2/287.2 (M − H)⁻ (ES⁻), at 4.32min, 98.0% (method B). (xi) 6-bromo-5-(4- 5-(4- Mass spectroscopy: (400MHz, DMSO) δ: (difluoromethoxy)phe- (difluoromethoxy)phe- m/z 317, 319(M + H)⁺ 7.30-7.36 (m, 2H), nyl)-1,2,4-triazin-3- nyl)-1,2,4-triazin-3-(ES⁺); 315-, 317 (M − H)⁻ 7.39 (t, 2JHF 72 Hz, amine (1.32 g, 50%) amine(2 g, 8.40 (ES⁻), at 3.98 min, 1H), 7.57 (s, 2H), mmol) 100% puritymethod B. 7.81-7.87 (m, 2H). (xii) 6-bromo-5-[4- 5-[4- HPLC purity:98.35% (400 MHz, DMSO) δ: (methoxymethyl)phe- (methoxymethyl)phe- (242nm); Mass 3.33 (s, 3H), 4.48 (s, nyl]-1,2,4-triazin-3-nyl]-1,2,4-triazin-3- spectroscopy: (ESI +ve) 2H), 7.44 (d, 2H), amine(1.3 g, 43%) amine (2.2 g, 15.2 295.0 [M + H]⁺. 7.54 (b s, 2H), 7.72mmol) (d, 2H). (xiii) 6-bromo-5-(3-chloro- 5-(3-chloro-4- Massspectroscopy: (400 MHz, DMSO) δ: 4-fluorophenyl)- fluorophenyl)-1,2,4-m/z 303, 305 (M + H)⁺ 7.54-7.70 (m, 3H), 1,2,4-triazin-3-aminetriazin-3-amine (2.2 g, (ES⁺); 301, 303 (M − H)⁻ 7.80 (ddd, J 8.6, 4.7,(1.12 g, 36%) 9.79 mmol) (ES⁻), at 4.35 min, 2.2 Hz, 1H), 7.99 (dd, 100%purity method B. J 7.2, 2.2 Hz, 1H). (xiv) 6-bromo-5-(3-chloro-5-(3-chloro-5- HPLC purity: 99.01% (400 MHz, CDCl₃) δ: 5-fluorophenyl)-fluorophenyl)-1,2,4- (247 nm); Mass 5.53 (bs, 2H), 7.271,2,4-triazin-3-amine triazin-3-amine (16.0 spectroscopy: (ESI +ve) (m,1H), 7.48 (m, 1H), (8.0 g, 38%) g, 55.55 mmol) 304.0 [M + H]⁺. 7.64 (m,1H). (xv) 6-bromo-5-(3,5- 5-(3,5- HPLC purity: 97.88% (400 MHz, CDCl₃)δ: difluorophenyl)- difluorophenyl)-1,2,4- (247 nm); Mass 7.48 (m, 3H),7.62 (s, 1,2,4-triazin-3-amine triazin-3-amine (18.0 spectroscopy: (ESI+ve) 2H). (6.0 g, 24%) g, 62.0 mmol) 286.8 [M + H]⁺. (xvi) 6-bromo-5-5-(pyrimidin-2-yl)- HPLC purity: 99.08% (400 MHz, DMSO) δ:(pyrimidin-2-yl)- 1,2,4-triazin-3-amine Mass spectroscopy: 7.73 (t, 1H),7.79 (s, 1,2,4-triazin-3-amine (1.0 g, 5.75 mmol) (ESI +ve) 253. [M +H]⁺. 2H), 9.04 (d, 2H) (0.90 g, 64%) and N- bromosuccinimide (1.53 g,8.60 mmol) (xvii) 6-bromo-5-(pyridin- 5-(pyridin-2-yl)-1,2,4- Massspectroscopy: 2-yl)-1,2,4-triazin-3- triazin-3-amine (0.30 (ESI +ve)253. [M + H]⁺. amine (0.18 g, 41%) g, 1.73 mmol) and N- TLC R_(f): 0.6(ethyl bromosuccinimide acetate) (0.46 g, 2.60 mmol) (xviii)6-bromo-5-(pyridin- 5-(pyridin-3-yl)-1,2,4- TLC R_(f): 0.6 (ethyl3-yl)-1,2,4-triazin-3- triazin-3-amine (0.4 g, acetate) amine (0.19 g,33%) 2.3 mmol) and N- Mass spectroscopy: bromosuccinimide (ESI +ve) 253.[M + H]⁺. (0.61 g, 3.4 mmol) (xix) 6-bromo-5-(4- 5-(4-methylphenyl)-Mass spectroscopy: m/z (400 MHz, DMSO) δ: methylphenyl)-1,2,4-1,2,4-triazin-3-amine 265.0/267.0 (M + H)⁺ 3.35 (s, 3H), 7.41 (m,triazin-3-amine (450 (930 mg, 5.0 mmol) (ESI+) at 3.0 min, >95% 2H),7.74 (m, 2H) mg, 34%) and N- (method C). (NH₂ not observed).bromosuccinimide (2.67 g, 15.0 mmol) (xx) 6-bromo-5-(4-5-(4-ethylphenyl)- Mass spectroscopy: m/z ethylphenyl)-1,2,4-1,2,4-triazin-3-amine 279.0/281.0 (M + H)⁺ triazin-3-amine (500 (930 mg,5.0 mmol) (ESI+) at 3.48 min, mg, crude; used and N- 90% (method C).without bromosuccinimide TLC R_(f): 0.11 chromatographic (2.67 g, 15.0mmol) (MeOH/DCM, 3:97) purification) (xxi) 6-bromo-5-(2-5-(2-fluorophenyl)- TLC R_(f): 0.4 (400 MHz, DMSO) fluorophenyl)-1,2,4-1,2,4-triazin-3-amine (EtOAc:isohexane 1:1) δ: 7.32-7.42 (m, 2H),triazin-3-amine (700 (2.5 g, 13.2 mmol) 7.54-7.67 (m, 4H) mg, 20%) andN- bromosuccinimide (7.05 g, 39.6 mmol) (xxii) 6-bromo-5-(2,5- 5-(2,5-Mass spectroscopy: (400 MHz, DMSO) difluorophenyl)-difluorophenyl)-1,2,4- m/z 288.9 (⁸¹Br) δ: 7.43-7.86 (m, 5H)1,2,4-triazin-3-amine triazin-3-amine (2.5 g, (M + H)⁺ (ES⁺), at 1.29(800 mg, 27%) 10.4 mmol) and N- min, 100% (method A) bromosuccinimide(7.05 g, 39.6 mmol) (xxiii) 6-bromo-5-(4- 5-(4-methoxyphenyl)- TLCR_(f): 0.4 (400 MHz, DMSO) methoxyphenyl)- 1,2,4-triazin-3-amine(EtOAc:isohexane 1:1) δ: 3.83 (s, 3H), 7.08 1,2,4-triazin-3-amine (2.5g, 12.4 mmol) (d, J 9.0, 2H), 7.47- (600 mg, 17%) and N- 7.54 (bs, 2H),7.80 (d, bromosuccinimide J 9.0, 2H) (7.05 g, 39.6 mmol)Preparation 44a: General Procedure for S_(N)Ar Displacements of 2-ChloropyridineDerivatives with Amines

A 2-chloropyridine derivative (1 equivalent) and an amine (typically 5equivalents) were dissolved in MeCN and sealed in a microwave vial. Themixture was heated under microwave irradiation (typically 160-180° C.)for up to 1 hour with LCMS monitoring. If necessary, further equivalentsof amine were added and the procedure repeated. Upon completion of thereaction, the mixture was evaporated under reduced pressure and purifiedby flash column chromatography, eluting with ethyl acetate/hexanemixtures, or by preparative HPLC.

The following intermediate compounds were prepared according to thegeneral procedure of Preparation 4a:

No. Product (yieid) Prepared from LC/MS NMR (i) 2- 2-Chloro-6- Massethyl(methyl)amino- methylpyridine (0.87 spectroscopy: m/z6-methylpyridine mL, 7.84 mmol) and 151 (M + H)⁺ (ES+) at (534 mg, 45%)ethylmethylamine 1.56 min, 95% (3.37 mL, 39.2 mmol) (method A) TLCR_(f): 0.55 (EtOAc/ isohexane, 1:20) (ii) 2-dimethylamino-6- 2-Chloro-6-Mass methylpyridine (93 methylpyridine (0.35 spectroscopy: m/z mg, 21%).mL, 3.20 mmol) and 137 (M + H)⁺ (ES)⁺ at dimethylamine (2.0M 1.37 min(method A) solution in THF, TLC R_(f): 0.38 (Et₂O/ 8.0 mL, 16.0 mmol)isohexane, 1:20) (iii) 2-(azetidin-1-yl)-6- 2-Chloro-6- Mass (400 MHz,CDCl₃) δ: (trifluoromethyl)pyri- trifluoromethylpyridine spectroscopy:m/z 2.41 (quint., J7.5, dine (807 mg, 72%) (1.00 g, 5.51 mmol) (ES⁺)223.0 (M + H)⁺ 2H), 4.08 (t, J7.5, and azetidine (1.57 g, at 1.68 min,4H), 6.36-6.39 (m, 1.86 ml, 27.5 mmol) 90% (method A) 1H), 6.89-6.91 (m,1H), 7.49-7.53 (m, 1H). (iv) 4-(6-methylpyridin- 2-Chloro-6- Mass (400MHz, CDCl₃) δ: 2-yl)morpholine methylpyridine spectroscopy: m/z 2.41 (s,3H), 3.48- (693 mg, 50%) (1.00 g, 0.87 ml, (ES⁺) 179.0 (M + H)⁺ 3.50 (m,4H), 3.81- 7.84 mmol) and at 1.26 min, 3.84 (m, 4H), 6.42- morpholine(3.41 g, 90% (method A). 6.44 (m, 1H), 6.53- 3.45 ml, 39.2 mmol) 6.55(m, 1H), 7.38- 7.42 (m, 1H).4b: Preparation of Other Pyridine Derivatives

(i) Preparation of 2,6-de-dimethylpyridine

Methyl-d₃-magnesium iodide solution (9.60 mL, 1 M in diethyl ether, 9.60mmol) was added drop-wise over 10 mins to a solution of2,6-dibromopyridine (947 mg, 4.00 mmol) and iron(III)acetylacetonate(141 mg, 0.40 mmol) in THF (30 mL) and NMP (3 mL) under N₂. Afterstirring at ambient temperature for 40 mins, 1 M aqueous HCl (10 mL) wasadded and the mixture stirred for 5 mins. Diethyl ether (20 mL) wasadded and the phases were separated. The organic phase was extractedwith water (2×10 mL) and the combined aqueous phases were then basifiedby the addition of 1M aqueous NaOH (15 mL). The aqueous phase wasextracted with DCM (3×25 mL) and the combined organic phasesconcentrated in vacuo. Purification by gradient flash chromatography(SiO₂, 5 to 20% EtOAc in isohexane) yielded the title compound as aclear oil (430 mg, 95%).

¹H NMR: (400 MHz, CDCl₃) δ: 6.95 (d, J=7.8, 2H), 7.45 (t, J=7.8, 1H).

TLC R_(f): 0.30 (EtOAc/isohexane, 1:4)

(ii) Preparation of 2-d₃-methyl-6-(trifluoromethyl)pyridine

A mixture of 2-chloro-6-(trifluoromethyl)pyridine (2.69 g, 14.8 mmol)and iron(III)acetylacetonate (523 mg, 1.48 mmol) in THF (100 mL) and NMP(10 mL) was stirred at 0° C. under N₂ for 5 mins. Methyl-d₃-magnesiumiodide solution (18.0 mL, 1M in diethyl ether, 18.0 mmol) was addeddrop-wise over 10 mins, and the mixture was stirred under N₂ at 0° C.for 5 mins, then ambient temperature for 75 mins, 1 M aqueous HCl (50mL) was added and the mixture was stirred for 5 mins before addition ofdiethyl ether (50 mL) and separation of the phases. The organic phasewas washed with 0.5 M aqueous HCl (50 mL) and water (50 mL) and thecombined aqueous phases were extracted with diethyl ether (2×50 mL). Thecombined organic phases were concentrated to a volume of approximately25 mL and short path distillation (bp 28-30° C. at 35 mbar) yielded aclear oil to which was added DCM (5 mL) and H₂O (5 mL). The phases wereseparated and the aqueous phase was extracted with DCM (2×5 mL); thecombined organic phases were concentrated in vacuo to yield the titlecompound (639 mg, 26%) as a clear oil.

¹H NMR: (400 MHz, CDCl₃) δ: 7.34 (d, J 7.8, 1H), 7.49 (d, J 7.8, 1H),7.75 (t, J 7.8, 1H).

Bp: 28-30° C. at 35 mbar

(iii) Preparation of 2-cyclopropyl-6-(trifluoromethyl)pyridine

2-Chloro-6-trifluoromethyl pyridine (451 mg, 2.5 mmol),cyclopropyltrifluoroborate potassium salt (373 mg, 2.52 mmol), palladiumacetate (11 mg, 0.05 mmol), di(1-adamantyl)-n-butylphosphine (27 mg,0.075 mmol), and cesium carbonate (2.4 g, 7.5 mmol) were suspended in amixture of toluene and water (10:1, 10 mL). After flushing the vesselunder a stream of nitrogen gas for 5 minutes, the reaction tube wassealed and then heated at 100° C. for 18 hours. On cooling, the mixturewas partitioned between DCM (15 mL) and water (15 mL). The separatedaqueous phase was extracted with DCM (2×15 mL) and the combined organicphases were passed through a phase separator and concentrated in vacuo,affording a yellow oil which was used without further purification (423mg, crude).

LCMS: major peak observed at 1.77 min; poor ionisation (method A)

TLC R_(f): 0.6 (EtOAc/hexane, 1:9).

(iv) Preparation of 2-ethyl-6-(trifluoromethyl)pyridine

2-Chloro-6-trifluoromethyl pyridine (451 mg, 2.5 mmol),ethyltrifluoroborate potassium salt (374 mg, 2.75 mmol), palladiumacetate (11 mg, 0.05 mmol), di(1-adamantyl)-n-butylphosphine (27 mg,0.075 mmol), and cesium carbonate (2.4 g, 7.5 mmol) were suspended in amixture of toluene and water (10:1, 10 mL). After flushing the vesselunder a stream of nitrogen gas for 5 minutes, the reaction tube wassealed and then heated at 100° C. for 18 hours. On cooling, the mixturewas partitioned between DCM (15 mL) and water (15 mL). The separatedaqueous phase was extracted with DCM (2×15 mL) and the combined organicphases were passed through a phase separator and concentrated in vacuo,affording a yellow oil which was used without further purification (460mg, crude)

LCMS: major peak observed at 1.53 min; poor ionisation (method A)

TLC R_(f): 0.55 (EtOAc/hexane, 1:9).

(v) Preparation of 2-ethylamino-6-methylpyridine

2-Amino-6-methylpyridine (1.00 g, 9.25 mmol) and acetaldehyde (0.52 mL,9.34 mmol) were stirred together in anhydrous methyl alcohol for 1 hourat room temperature under a nitrogen atmosphere. The mixture was thentreated with sodium triacetoxyborohydride (7.84 g, 37.0 mmol) and fivedrops of acetic acid and all was allowed to continue stirring for 4hours. The reaction mixture was concentrated in vacuo. The residue waspartitioned between water and DCM, and the separated aqueous phase wasextracted twice with DCM. The combined organics were dried over MgSO₄,filtered and concentrated in vacuo to give a mobile oil which waspurified by flash column chromatography, eluting with 2% MeOH/DCM, togive 2-ethylamino-6-methylpyridine (636 mg, 51%).

LCMS: 137.0 [M+H]⁺ (ES+) at 1.17 min, 100% (method A).

Preparation 5

General Procedure for the Preparation of 2-FluoromethylpyridineDerivatives

(Diethylamino)sulfur trifluoride (1.0 mL, 7.7 mmol) was added to asolution of a 2-pyridinylmethanol derivative (7.0 mmol) in DCM (30 mL,anhydrous), drop-wise, under nitrogen in an acetone/CO₂ bath at −20° C.The resultant solution was allowed to warm to ambient temperature andthen stirred until complete conversion was observed by TLC. The reactionwas quenched with ice and then basified to pH 8-10 with solid sodiumhydrogen carbonate. The layers were then separated, and the organicphase washed successively with water and then saturated brine solution,then dried (MgSO₄), concentrated in vacuo and purified by gradient flashchromatography, affording the 2-fluoromethylpyridine derivative.

The following intermediate compounds were prepared according to thegeneral procedure of Preparation 5:

No. Product (yield) Prepared from LCMS/TLC NMR (i) 2-(fluoromethyl)-6-6-methyl-2- TLC R_(f): 0.9 (400 MHz, DMSO) methylpyridine (850 mg,pyridine (EtOAc/iso- δ: 2.48 (s, 3H), 5.43 (d, 84%) methanol (1.0 g,hexane 1:9) J 47.2 2H), 7.23 (d, J 8.1 mmol) 7.8, 1H), 7.29 (d, J 7.8,1H), 7.76 (t, J 7.8, 1H) (ii) 2-chloro-6- (6-chloro-2- TLC R_(f): 0.9(400 MHz, DMSO) (fluoromethyl)pyridine pyridinyl)methanol (EtOAc/iso- δ:5.51 (d, J 46.7 Hz, (200 mg, 17%) (1.0 g, 7.0 hexane 1:9) 2H), 7.55 (d,J 7.78, mmol) 1H), 7.57 (d, J 7.78, 1H), 8.00 (t, J 7.78, 1H) (iii)2,6-bis- 2,6- TLC R_(f): 0.9 (400 MHz, DMSO) (fluoromethyl)pyridinebis(hydroxymeth- (EtOAc/iso- δ: 5.50 (d, J 46.6, 2H), (850 mg, 41%)yl)pyridine (2.0 hexane 1:9) (d, J 7.78, 2H), 7.98 (t, g, 14.4 mmol) J7.78, 1H)Preparation 6General Procedure for the Preparation of 2-DifluoromethylpyridineDerivatives

(Diethylamino)sulfur trifluoride (2.4 mL, 18.3 mmol) was added to asolution of a 2-pyridinecarboxaldehyde derivative (8.3 mmol) in DCM (30mL, anhydrous), drop-wise, under nitrogen in an acetone/CO₂ bath at −20°C. The resultant solution was allowed to warm to ambient temperature andthen stirred until complete conversion was observed by TLC. The reactionwas quenched with ice and then basified to pH 8-10 with solid sodiumhydrogen carbonate. The layers were then separated, and the organicphase washed successively with water and then saturated brine solution,then dried (MgSO₄), concentrated in vacuo and purified by gradient flashchromatography, affording the 2-fluoromethylpyridine derivative.

The following intermediate compounds were prepared according to thegeneral procedure of Preparation 6:

No. Product (yield) Prepared from LCMS/TLC NMR (i) 2-chloro-6-6-chloro-2- TLC R_(f): 0.9 (400 MHz, DMSO), δ: (difluoromethyl)pyridinepyridinecarboxal- (EtOAc/ 4.69 (s, 1H), 7.50 (m, (1.1 g, 86%) dehyde(1.0 g, isohexane 2H), 7.91 (m, 1H) 7.07 mmol) 1:9) (ii)2-(difluoromethyl)-6- 6-methyl-2- TLC R_(f): 0.9 (400 MHz, DMSO), δ:methylpyridine (410 mg, pyridinecarboxal- (EtOAc/ 2.53 (3H, s) 6.90 (d,J 35%) dehyde (1.0 g, isohexane 55.2, 1H), 7.47 (m, 8.26 mmol) 1:9) 2H),7.89 (m, 1H)Preparation 7General Procedure for the 4-Borylation of 2,6-Disubstituted PyridineDerivatives

Methoxy(cyclooctadiene)rhodium(I) dimer (0.05 molar equivalents Rh),4,4′-di-tert-butyl-2,2′-bipyridine(dtbpy) (0.05 molar equivalents), andbis(pinacolato)diboron (2 molar equivalents) were added to a flask whichhad been thoroughly purged with nitrogen. The flask was once more purgedbefore adding hexane via syringe (final concentration of pyrineapproximately 0.5 mM). The resulting mixture was heated at 50° C. for 10minutes until the appearance of a dark red solution was observed. Apyridine derivative (1 molar equivalent) was then added by syringe andheating continued for a further 6 hours. After cooling to roomtemperature, the crude reaction mixture concentrated under reducedpressure. The resulting residue was purified by column chromatography,eluting with ethyl acetate/hexane mixtures to afford the targetcompound.

The following compounds were prepared according to the general procedureof Preparation 7, by reacting the indicated starting materials for 6hours at 50° C., unless otherwise stated:

No. Product (yield) Prepared from LCMS/TLC NMR (i) 2,6-d₆-dimethyl-4-bis(pinacolato)diboron Mass (4,4,5,5-tetramethyl- (1.93 g, 7.60 mmol)and spectroscopy: 1,3,2-dioxaborolan- 2,6-d₆-dimethylpyridine m/z 240.12-yl)pyridine (1.56 g, (430 mg, 3.80 mmol) [M + H]⁺ (ESI +ve) crude)used without were heated at 70° C. for at 0.1 min, chromatographic 105minutes according to 100% (method purification the typical procedure.A). (ii) 2-d₃-methyl-4- 2-d₃-methyl-6- Mass (400 MHz,(4,4,5,5-tetramethyl- (trifluoromethyl)pyridine spectroscopy: CDCl₃) δ:1.37 1,3,2-dioxaborolan- (639 mg, 3.89 mmol) and m/z: 291.1 (s, 12H),7.70 2-yl)-6- bis(pinacolato)diboron [M + H]⁺ (ESI +ve) (s, 1H), 7.82(trifluoromethyl)pyri- (1.98 g, 7.80 mmol) were at 0.15 (s, 1H). dine(716 mg, 32%) heated at 70° C. for 3.5 min, 100% hours according to the(method A) typical procedure. (iii) 2-ethylamino-4- bis(pinacolato)diborane Mass (4,4,5,5-tetramethyl- (776 mg, 3.06 mmol) andspectroscopy: 1,3,2-dioxaborolan- 2-ethylamino-6- m/z 263.2 2-yl)-6-methylpyridine (277 mg, [M + H]⁺ (ESI+) at methylpyridine 2.04 mmol)were heated 0.10 min, (crude sample used to 55° C. for 6 hours (methodA). without according to the typical chromatographic procedure.purification) (iv) 2- bis(pinacolato)diboron Mass ethyl(methyl)amino-(1.81 g, 7.11 mmol) and spectroscopy: 4-(4,4,5,5-2-ethyl(methyl)amino-6- m/z 277 (M + H)⁺ tetramethyl-1,3,2-methylpyridine (534 mg, (ES)⁺ at 1.11 dioxaborolan-2-yl)-6- 3.55 mmol)were heated min, (method A). methylpyridine (2.04 at 65° C. for 3 hoursg, crude) used according to the typical without procedure.chromatographic purification. (v) 2-dimethylamino-4- 2-dimethylamino-6-No ionisation (4,4,5,5-tetramethyl- methylpyridine (93 mg, observed by1,3,2-dioxaborolan- 0.68 mmol) and LCMS, major 2-yl)-6-bis(pinacolato)diboron peak at 0.8 min methylpyridine (414 (348 mg g,1.37 mmol) (method A). mg, crude) used were heated at 70° C. for without2 hours according to the chromatographic typical procedure.purification. (vi) 2-chloro-4-(4,4,5,5- 2-methyl-6-chloro HPLC purity:(400 MHz, tetramethyl-1,3,2- pyridine (25 g, 195.9 99.33% (282 nm) DMSO)δ: 1.30 dioxaborolan-2-yl)-6- mmol) and Mass (s, 12 H), 2.50methylpyridine (46.9 bis(pinacolato)diboron spectroscopy: (s, 3H), 7.35g, 94%) (32.3 g, 127 mmol) (ESI +ve) 254.1 (s, 1H), 7.44 according tothe typical [M + H]⁺. (s, 1H). procedure. (vii) 2,6-dimethyl-4-2,6-dimethyl pyridine (1.5 HPLC purity: (400 MHz, (4,4,5,5-tetramethyl-g, 13.9 mmol) and 93.33% (268 nm) DMSO) δ: 1.27 1,3,2-dioxaborolan-bis(pinacolato)diboron Mass (s, 12 H), 2.48 2-yl)pyridine (1.0 g, (1.9g, 7.69 mmol) spectroscopy: (s, 6H), 7.20 30%) according to the typical(ESI +ve) 234.1 (s, 2H). procedure. [M + H]⁺. (viii)2-(trifluoromethyl)-4- 2-trifluoromethyl-6- HPLC purity: (400 MHz,(4,4,5,5-tetramethyl- methyl pyridine (4.0 g, 95.65% (210 nm) DMSO) δ:1.31 1,3,2-dioxaborolan- 24.8 mmol) and Mass (s, 12 H), 2.51 2-yl)-6-bis(pinacolato)diboron spectroscopy: (s, 3H), 7.70 methylpyridine (5.9(4.09 g, 16.1 mmol) (ESI +ve) 287.8 (s, 1H), 7.76 g, 83%) according tothe typical [M + H]⁺. (s, 1H). procedure. (ix) 2-dimethylamino-4-N,N-dimethylpyridine-2- Mass (4,4,5,5-tetramethyl- amine (0.9 g, 7.4mmol) spectroscopy: 1,3,2-dioxaborolan- and (ESI +ve) 248.92-yl)pyridine (0.98 g, bis(pinacolato)diboron [M]⁺). 53%) (1.12 g, 4.4mmol) TLC R_(f): 0.10 according to the typical (ethyl acetate/procedure. hexane, 5:5) (x) 2-bromo-4-(4,4,5,5- 2-methyl-6-bromo Masstetramethyl-1,3,2- pyridine (0.50 g, 2.90 spectroscopy:dioxaborolan-2-yl)-6- mmol) and (ESI +ve) 299.7 methylpyridine (0.70bis(pinacolato)diboron [M + H]⁺ g, 81%) (0.48 g, 1.8 mmol) TLC R_(f):0.15 according to the typical (ethyl acetate/ procedure. hexane, 5:5)(xi) 2-cyano-4-(4,4,5,5- 2-methyl-6-cyano Mass tetramethyl-1,3,2-pyridine (0.5 g, 4.2 spectroscopy: dioxaborolan-2-yl)-6- mmol) and (ESI+ve) 244.9 methylpyridine (0.70 bis(pinacolato)diboron [M + H]⁺ g, 70%)(0.69 g, 2.7 mmol), TLC R_(f): 0.15, (ethyl acetate/ hexane, 5:5) (xii)1-oxo-2,6-dimethyl- 2,6-dimethyl pyridine-N- Mass 4-(4,4,5,5- oxide (1.0g, 8.12 mmol) spectroscopy: tetramethyl-1,3,2- and (ESI +ve) 249.9dioxaborolan-2- bis(pinacolato)diboron [M]⁺ yl)pyridine (1.8 g, (1.34 g,5.27 mmol) TLC R_(f): 0.12 90%) (ethyl acetate/ hexane, 5:5) (xiii)2-bromo-4-(4,4,5,5- 2-trifluoro methyl 6- Mass tetramethyl-1,3,2- bromopyridine (0.5 g, spectroscopy: dioxaborolan-2-yl)-6- 2.20 mmol) and (ESI+ve) 352.9 trifluoromethylpyridine bis(pinacolato)diboron [M]⁺). (0.5 g,64%) (0.36 g, 1.4 mmol) TLC R_(f): 0.18 according to the typical (ethylacetate/ procedure. hexane, 5:5) (xiv) 2-chloro-4-(4,4,5,5- 2-chloro-6-TLC R_(f): streak (400 MHz, tetramethyl-1,3,2- (difluoromethyl)pyridinefrom baseline to DMSO) dioxaborolan-2-yl)-6- (1.4 g, 8.56 mmol) and 0.3(EtOAc/ δ: 1.33 (s, (difluoromethyl)pyridine bis(pinacolato)diboronisohexane, 1:9) 12H), 7.03 (t, J (310 mg, 13%) (10.1 g, 42.8 mmol) were54.5, 1H), 7.75 heated at 60° C. for 2 (s, 1H), 7.80 hours according tothe (s, 1H) typical procedure. (xv) 2-(fluoromethyl)-4-2-(fluoromethyl)-6- Mass (400 MHz, (4,4,5,5-tetramethyl- methylpyridine(2.1 g, spectroscopy: DMSO) 1,3,2-dioxaborolan- 16.8 mmol) and (ESI +ve)252.1 δ: 1.32 (s, 2-yl)-6- bis(pinacolato)diboron [M + H]⁺ at 0.13 12H),2.55 (s, methylpyridine (1.1 (8.5 g, 33.6 mmol) were mins, (method 3H),5.45 (d, J g, 26%) heated at 60° C. for 48 A). 47.2, 2H), 7.45 hoursaccording to the (s, 1H), 7.47 typical procedure. (s, 1H) (xvi)2-chloro-4-(4,4,5,5- 2-chloro-6- TLC R_(f): streak (400 MHz,tetramethyl-1,3,2- (fluoromethyl)pyridine from baseline to DMSO)dioxaborolan-2-yl)-6- (1.0 g, 6.9 mmol) and 0.3 (EtOAc/ δ: 1.33 (s,(fluoromethyl)pyridine bis(pinacolato)diboron isohexane, 1:9) 12H),5.50(d, J (450 mg, 24%) (3.5 g, 13.8 mmol) were 46.7, 2H), 7.57 heatedat 60° C. for 2 (s, 1H), 7.65 hours according to the (s, 1H) typicalprocedure. (xvii) 2,6-bis- 2,6-bis- TLC R_(f): streak (400 MHz,(fluoromethyl)-4- fluoromethylpyridine from baseline to DMSO)(4,4,5,5-tetramethyl- (1.2 g, 6.8 mmol) and 0.3 δ: 1.22 (s,1,3,2-dioxaborolan- bis(pinacolato)diboron (EtOAc/isohexane, 12H), 5.50(d, 2-yl)-pyridine (1.6 g, (3.5 g, 13.6 mmol) were 1:9) J 46.7, 4H),88%) heated at 65° C. for 2 7.51 (s, 2H) hours according to the typicalprocedure. (xviii) 2-(difluoromethyl)-4- 2-(difluoromethyl)-6- TLCR_(f): streak (400 MHz, (4,4,5,5-tetramethyl- methylpyridine (1.2 g, 8.4from baseline to DMSO) 1,3,2-dioxaborolan- mmol) and 0.3 δ: 1.32 (s,2-yl)-6- bis(pinacolato)diboron (EtOAc/isohexane, 12H), 2.55 (s,methylpyridine (500 (4.3 g, 16.8 mmol) were 1:9) 3H), 6.94 (t, J mg,22%) heated at 60° C. for 2 55, 1H), 7.61 hours according to the (s,1H), 7.63 typical procedure. (s, 1H) (xix) 2-ethyl-4-(4,4,5,5-2-ethyl-6- Mass (400 MHz, tetramethyl-1,3,2- (trifluoromethyl)pyridinespectroscopy: DMSO) δ: 1.25 dioxaborolan-2-yl)-6- (440 mg, 2.50 mmol)and m/z 302.1 (t, 3H, J 8.0), (trifluoromethyl)pyridinebis(pinacolato)diboron (M + H)⁺ (ES+); 1.33 (s, 12H), (551 mg, 73%)(1.27 g, 5.00 mmol) at 0.93 min 2.88 (q, 2H, J according to the typical(method A). 8.0), 7.74 (s, procedure. 1H), 7.77 (s, 1H). (xx)2-cyclopropyl-4- 2-cyclopropyl-6- Mass (400 MHz, (4,4,5,5-tetramethyl-(trifluoromethyl)pyridine spectroscopy: DMSO) δ: 0.92-1,3,2-dioxaborolan- (423 mg, 2.25 mmol) and m/z 314.1 0.97 (m, 2H),2-yl)-6- bis(pinacolato)diboron (M + H)⁺ (ES+); 1.02-1.08 (m,(trifluoromethyl)pyridine (1.14 g, 4.50 mmol) at 1.02 min 2H), 1.33 (s,(473 mg, 67%) according to the typical (method A). 12H), 2.29-procedure. 2.36 (m, 1H), 7.63 (s, 1H), 7.79 (s, 1H). (xxi)2-(azetidin-1-yl)-6- 2-(azetidin-1-yl)-6- Mass (400 MHz,trifluoromethyl-4- (trifluoromethyl)pyridine spectroscopy: CDCl₃) δ:1.31 (4,4,5,5-tetramethyl- (807 mg, 3.99 mmol) and m/z 329.0 (s, 12H),2.35 1,3,2-dioxaborolan- bis(pinacolato)diboron (M + H)⁺ (ES⁺), at(quint., J 7.5, 2-yl)pyridine (68%) (2.03 g, 7.98 mmol) were 1.00 min,2H), 4.03 (t, J heated at 70° C. for 2.0 98% (method 7.5 Hz, 4H), hoursaccording to the A). 6.74 (s, 1H), typical procedure. 7.06 (s, 1H).(xxii) 2-methyl-6- 4-(6-methylpyridin-2- Mass (morpholin-4-yl)-4-yl)morpholine spectroscopy: (4,4,5,5-tetramethyl- (693 mg, 3.89 mmol)m/z 305.0 1,3,2-dioxaborolan- and (M + H)⁺ (ES⁺), at 2-yl)pyridine (1.09g, bis(pinacolato)diboron 2.02 min, 92%) (1.97 g, 7.78 mmol) were ~80%(method heated at 70° C. for 4.0 A). hours according to the TLC R_(f):0.3 typical procedure (DCM/MeOH, 1:9 (5% NH₃)) (xxiii)2-chloro-4-(4,4,5,5- bis(pinacolato)diboron HPLC purity (400 MHz,tetramethyl-1,3,2- (1.99 g, 7.9 mmol) and 2- purity: 95.87% DMSO) δ:1.31 dioxaborolan-2-yl)-6- trifluoromethyl-6- (273 nm) (s, 12 H), 7.88trifluoromethylpyridine chloropyridine (2.2 g, Mass (s, 1H), 7.89 (2.6g, 68%). 12.1 mmol) spectroscopy: (s, 1H). (ESI +ve) 308.1[M + H]⁺.

Example 1

General Procedure for the Preparation of5,6-Biaryl-3-amino-1,2,4-triazines

A solution of intermediate D, a 6-halo-5-aryl-1,2,4-triazin-3-aminederivative, (0.80 mmol) in dioxane (2 mL) is treated with an arylboronicacid (0.92 mmol) and K₂CO₃ (0.23 g, 1.67 mmol). The resulting mixture isdiluted with water (1.0 mL), degassed, treated with tetrakistriphenylphosphine palladium (0.05 g, 0.04 mmol) and stirred at 150° C.for 2.25 hrs with monitoring by TLC (hexane/ethyl acetate, 5:5). Uponcompletion of the reaction, the mixture is diluted with water (30 mL)and extracted with ethyl acetate (3×20 mL); the combined organicextracts are then dried over Na₂SO₄ and concentrated under reducedpressure. The crude compound, product A, is purified by gradient flashchromatography or preparative HPLC.

(i) 5,6-Diphenyl-1,2,4-triazin-3-amine

5,6-Diphenyl-1,2,4-triazin-3-amine (86.0 mg, 42%) was prepared from6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.8 mmol) and phenylboronic acid (0.11 g, 0.92 mmol) according to the general procedure ofExample 1.

HPLC purity: 99.6% (261 nm)

Mass spectroscopy: (ESI+ve) 249.0 [M+H]⁺.

¹H NMR: (400 MHz. CDCl₃) δ: 5.49 (s, 2H), 7.30-7.37 (m, 5H), 7.40-7.43(m, 3H,) 7.45-7.46 (m, 1H), 7.47-7.51 (m, 1H).

(ii) 6-(3-Methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (106 mg, 47%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.8 mmol)and 3-methoxyphenyl boronic acid (0.137 g, 0.90 mmol) according to thegeneral procedure of Example 1.

HPLC purity: 99.58% (223 nm)

Mass spectroscopy: (ESI+ve) 278.9 [M+H]⁺.

¹H NMR: (400 MHz, CDCl₃) δ: 3.72 (s, 3H), 5.47 (s, 2H), 6.88-6.94 (m,2H), 7.03 (m, 1H), 7.20 (t, 1H), 7.33 (m, 2H), 7.40 (m, 1H), 7.44 (m,2H).

(iii) 6-(4-Fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(4-Fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine (99 mg, 46%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol)and 4-fluorophenylboronic acid (0.112 g, 0.80 mmol) according to thegeneral procedure of Example 1.

HPLC purity: 99.93% (261 nm)

Mass spectroscopy: (ESI+ve) 267.0 [M+H]⁺.

¹H NMR: (400 MHz, CDCl₃) δ: 5.49 (s, 2H), 6.99 (m, 2H), 7.31-7.37 (m,2H), 7.37-7.46 (m, 5H).

(iv) 6(5-Chloro-2-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(5-Chloro-2-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (57 mg, 22%)was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80mmol) and 5-chloro-2-methoxyphenylboronic acid (0.15 g, 0.80 mmol)according to the general procedure of Example 1.

HPLC purity: 98.73% (229 nm)

Mass spectroscopy: (ESI+ve) 312.9 [M]⁺.

¹H NMR: (400 MHz, CDCl₃) δ: 3.16 (s, 3H), 5.46 (s, 2H), 6.62 (d, 1H),7.26-7.33 (m, 3H), 7.37 (m, 1H), 7.44 (m, 2H), 7.66 (d, 1H).

(v) 6-(2-Chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(2-Chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine (103 mg, 45%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol)and 2-chlorophenylboronic acid (0.125 g, 0.80 mmol) according to thegeneral procedure of Example 1.

HPLC purity: 99.27% (245 nm)

Mass spectroscopy: (ESI+ve) 282.9 [M]⁺.

¹H NMR: (400 MHz, CDCl₃) δ: 5.62 (s, 2H), 7.26-7.32 (m, 2H), 7.33-7.36(m, 4H) 7.43-7.45 (m, 2H), 7.52 (m, 1H).

(vi) 6-(3-Chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine (110 mg, 49%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol)and 3-chlorophenylboronic acid (0.12 g, 0.80 mmol) according to thegeneral procedure of Example 1.

HPLC purity: 93.7% (261 nm)

Mass spectroscopy: (ESI+ve) 282.9 [M]⁺.

¹H NMR: (400 MHz, CDCl₃) δ: 5.50 (s, 2H), 7.18-7.26 (m, 2H), 7.30-7.36(m, 3H) 7.42-7.47 (m, 3H), 7.53 (s, 1H).

(vii) 6-(4-Chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(4-Chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine (125 mg, 56%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol)and 4-chlorophenylboronic acid (0.12 g, 0.80 mmol) according to thegeneral procedure of Example 1.

HPLC purity: 97.7% (264 nm)

Mass spectroscopy: (ESI+ve) 282.9 [M]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 5.46 (s, 2H), 7.28-7.33 (m, 2H), 7.35-7.38(m, 5H) 7.42-7.46 (m, 2H).

(viii) 6-(Furan-2-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(Furan-2-yl)-5-phenyl-1,2,4-triazin-3-amine (100 mg, 35%) was preparedfrom 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.3 g, 1.19 mmol) and2-furanboronic acid (0.16 g, 1.428 mmol) according to the generalprocedure of Example 1.

HPLC purity: 95.03% (290 nm)

Mass spectroscopy: (ESI+ve) 239.0 [M+H]⁺

¹H NMR: (400 MHz. CDCl₃) δ: 5.58 (s, 2H), 6.43 (m, 1H), 6.55 (m, 1H)7.40-7.47 (m, 3H), 7.47-7.59 (m, 3H).

(ix) 5-Phenyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazin-3-amine

5-Phenyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazin-3-amine (120 mg,31%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g,1.19 mmol) and 3-trifluoromethylphenylboronic acid (0.25 g, 1.30 mmol)according to the general procedure of Example 1.

HPLC purity: 99.4% (262 nm)

Mass spectroscopy: (ESI+ve) 316.9 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 7.36 (m, 4H), 7.42 (m, 2H), 7.51 (s, 2H) 7.56(m, 1H), 7.63 (m, 3H).

(x)6-[3-Fluoro-5-(trifluoromethyl)phenyl]-5-phenyl-1,2,4-triazin-3-amine

6-[3-Fluoro-5-(trifluoromethyl)phenyl-5-phenyl]-5-phenyl-1,2,4-triazin-3-amine(149 mg, 37%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine(0.30 g, 1.19 mmol) and 3-fluoro-5-(trifluoromethyl)phenylboronic acid(0.27 g, 1.30 mmol) according to the general procedure of Example 1.

HPLC purity: 94.3% (265 nm)

Mass spectroscopy: (ESI+ve) 335.0 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 7.36 (m, 4H), 7.45 (m, 3H), 7.61 (s, 2H) 7.64(d, 1H).

(xi) 5-Phenyl-6-(3,4,5-trifluorophenyl)-1,2,4-triazin-3-amine

5-Phenyl-6-(3,4,5-trifluorophenyl)-1,2,4-triazin-3-amine (131 mg, 37%)was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19mmol) and 3,4,5-trifluorophenylboronic acid (0.23 g, 1.30 mmol)according to the general procedure of Example 1.

HPLC purity: 99.6% (262 nm)

Mass spectroscopy: (ESI+ve) 303.0 [M+H]⁺, (ESI−ve) 301.2 [M−H]⁻

¹H NMR: (400 MHz, DMSO) δ: 7.24 (t, 2H), 7.38 (m, 4H), 7.44 (m, 1H),7.56 (s, 2H).

(xii) 6-(3,5-Difluorophenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(3,5-Difluorophenyl)-5-phenyl-1,2,4-triazin-3-amine (160 mg, 47%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol)and 3,5-difluorophenylboronic acid (0.20 g, 1.30 mmol) according to thegeneral procedure of Example 1.

HPLC purity: 99.3% (262 nm)

Mass spectroscopy: (ESI+ve) 284.9[M+H], (ESI−ve) 283.1 [M−H]⁻

¹H NMR: (400 MHz, DMSO) δ: 6.99 (d, 2H), 7.12 (t, 1H), 7.40 (m, 5H) 7.56(s, 2H).

(xiii) 6-(3,5-Dichlorophenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(3,5-Dichlorophenyl)-5-phenyl-1,2,4-triazin-3-amine (130 mg, 34%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol)and 3,5-dichlorophenylboronic acid (0.42 g, 2.19 mmol) according to thegeneral procedure of Example 1.

HPLC purity: 90% (245 nm)

Mass spectroscopy: (ESI+ve) 316.9[M+H]⁺, (ESI−ve) 315.1 [M−H]⁻

¹H NMR: (400 MHz, CDCl₃) δ: 5.55 (s, 2H), 7.33 (m, 3H), 7.38 (m, 2H)7.49 (m, 3H).

(xiv) 6-(5-Chloropyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(5-Chloropyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine (35 mg, 10%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol)and 5-chloropyridine-3-ylboronic acid (0.20 g, 1.30 mmol) according tothe general procedure of Example 1.

HPLC purity: 98.9% (262 nm)

Mass spectroscopy: (ESI+ve) 283.9 [M+H]⁺.

¹H NMR: (400 MHz, DMSO) δ: 7.38 (m, 4H), 7.45 (m, 1H), 7.61 (s, 2H),7.87 (t, 1H), 8.35 (d, 1H), 8.55 (d, 1H).

(xv) 6-(3-Chloro-4-fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Chloro-4-fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine (140 mg, 29%)was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59mmol) and 3-chloro-4-fluorophenylboronic acid (0.33 g, 1.91 mmol)according to the general procedure of Example 1.

HPLC purity: 93.7% (261 nm)

Mass spectroscopy: (ESI+ve) 300.9 [M+H]⁺.

¹H NMR: (400 MHz, CDCl₃) δ: 5.49 (s, 2H), 7.04 (t, 1H), 7.18 (m, 1H),7.37 (m, 2H), 7.45 (m, 3H), 7.60 (dd, 1H).

(xvi) 6-(3-Chloro-5-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Chloro-5-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (36 mg, 9%)was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19mmol) and 3-chloro-5-methoxyphenylboronic acid (0.27 g, 1.43 mmol)according to the general procedure of Example 1.

HPLC purity: 99% (254 nm)

Mass spectroscopy: (ESI+ve) 312.9 [M+H]⁺.

¹H NMR: (400 MHz. DMSO) δ: 3.63 (s, 3H), 6.78 (m, 1H), 6.94 (m, 2H),7.34-7.45 (m, 5H), 7.49 (bs, 2H).

(xvii) 6-(3-Fluoro-5-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Fluoro-5-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (193 mg,32%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g,1.99 mmol) and 3-fluoro-5-methoxy phenylboronic acid (0.37 g, 2.19 mmol)according to the general procedure of Example 1.

HPLC purity: 99.6% (263 nm)

Mass spectroscopy: (ESI+ve) 296.9 [M+H]⁺.

¹H NMR: (400 MHz, CDCl₃) δ: 3.69 (s, 3H), 5.56 (s, 2H), 6.59 (d, 1H)6.70 (d, 1H), 6.78 (s, 1H), 7.35 (m, 2H), 7.45 (m, 3H).

(xviii) 6-(1H-Indol-6-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(1H-Indol-6-yl)-5-phenyl-1,2,4-triazin-3-amine (107 mg, 23%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.4 g, 1.59 mmol)and indol-6-boronic acid (0.256 g, 1.59 mmol) according to the generalprocedure of Example 1.

HPLC purity: 97.75% (222 nm)

Mass spectroscopy: (ESI+ve) 288.0 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 6.38 (m, 1H), 6.89 (dd, 1H), 7.26-7.40 (m,3H), 7.42-7.62 (m, 5H), 11.12 (s, 1H).

(xix) 6-(3-Bromophenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Bromophenyl)-5-phenyl-1,2,4-triazin-3-amine (218 mg, 52%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.4 g, 1.59 mmol)and 3-bromophenylboronic acid (0.32 g, 1.59 mmol) according to thegeneral procedure of Example 1.

HPLC purity: 95.65% (262 nm)

Mass spectroscopy: (ESI+ve) 326.9 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 5.61 (s, 2H), 7.15 (t, 1H), 7.24 (m, 1H),7.35 (m, 2H), 7.47 (m, 4H), 7.69 (t, 1H).

(xx) 6-(3,4-Dichlorophenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(3,4-Dichlorophenyl)-5-phenyl-1,2,4-triazin-3-amine (52 mg, 54%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol)and 3,4-dichlorophenylboronic acid (65.5 mg, 0.344 mmol) according tothe general procedure of Example 1.

HPLC purity: 99.2% (254 nm)

Mass spectroscopy: (ESI+ve) 317.1/319.1/321.1 (M+H)⁺

¹H NMR: (400 MHz, d6-DMSO) δ: 7.24 (dd, 1H), 7.35-7.47 (m, 5H), 7.53(bs, 2H), 7.57 (m, 1H), 7.63 (d, 1H).

(xxi) 6-(3-Fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine (49 mg, 62%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol)and 3-fluorophenylboronic acid (48.1 mg, 0.344 mmol) according to thegeneral procedure of Example 1.

HPLC purity: 100% (254 nm)

Mass spectroscopy: (ESI+ve) 267.1 (M+H)⁺

¹H NMR: (400 MHz, d6-DMSO) 5:7.10-7.20 (m, 3H), 7.31-7.44 (m, 6H), 7.45(bs, 2H).

(xxii) 6-(1,3-Benzodioxol-5-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(1,3-Benzodioxol-5-yl)-5-phenyl-1,2,4-triazin-3-amine (54 mg, 62%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol)and benzo[d][1,3]dioxol-5-ylboronic acid (57.0 mg, 0.344 mmol) accordingto the general procedure of Example 1.

HPLC purity: 100% (254 nm)

Mass spectroscopy: 293.2 (M+H)⁺

¹H NMR: (400 MHz, d6-DMSO) δ: 6.05 (s, 2H), 6.52 (dd, 1H), 6.83 (m, 1H),6.87 (m, 1H), 7.32 (bs, 2H), 7.35-7.43 (m, 5H).

(xxiii) 3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)benzonitrile

3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)benzonitrile (20 mg, 25%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol)and 3-cyanophenylboronic acid (50.5 mg, 0.344 mmol) according to thegeneral procedure of Example 1.

HPLC purity: 96.0% (254 nm)

Mass spectroscopy: (ESI+ve) 274.2 (M+H)⁺

¹H NMR: (400 MHz, d6-DMSO) δ: 7.30-7.35 (m, 4H), 7.52 (m, 1H), 7.52 (m,1H), 7.54 (bs, 2H), 7.63 (m, 1H), 7.82 (m, 2H).

(xxiv) 6-(3,5-Dimethoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(3,5-Dimethoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (55 mg, 60%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol)and 3,5-dimethoxyphenylboronic acid (62.5 mg, 0.344 mmol) according tothe general procedure of Example 1.

HPLC purity: 100% (254 nm)

Mass spectroscopy: (ESI+ve) 309.2 (M+H)⁺

¹H NMR: (400 MHz, d6-DMSO) δ: 3.70 (s, 6H), 6.54 (m, 3H), 7.42-7.54 (m,7H).

(xxv) 6-(3,5-Dimethylphenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(3,5-Dimethylphenyl)-5-phenyl-1,2,4-triazin-3-amine (54 mg, 65%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol)and 3,5-dimethylphenylboronic acid (51.5 mg, 0.344 mmol) according tothe general procedure of Example 1.

HPLC purity: 100% (254 nm)

Mass spectroscopy: (ESI+ve) 277.2 (M+H)⁺

¹H NMR: (400 MHz, d6-DMSO) δ: 2.06 (s, 6H), 6.82 (m, 3H), 7.18-7.27 (m,7H).

(xxvi) 6-(3,4-Dimethylphenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(3,4-Dimethylphenyl)-5-phenyl-1,2,4-triazin-3-amine (55 mg, 67%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol)and 3,4-dimethylphenylboronic acid (51.5 mg, 0.344 mmol) according tothe general procedure of Example 1.

HPLC purity: 100% (254 nm)

Mass spectroscopy: (ESI+ve) 277.2 (M+H)⁺

¹H NMR: (400 MHz, d6-DMSO) δ: 2.15 (s, 3H), 2.17 (s, 3H), 6.88 (m, 1H),7.02 (m, 1H), 7.23 (m, 1H), 7.32 (bs, 2H), 7.34 (m, 2H), 7.87-7.42 (m,3H).

(xxvii) 6-[3-(Dimethylamino)phenyl]-5-phenyl-1,2,4-triazin-3-amine

6-[3-(Dimethylamino)phenyl]-5-phenyl-5-phenyl-1,2,4-triazin-3-amine (53mg, 60%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75mg, 0.299 mmol) and 3-(dimethylamino)phenylboronic acid (56.7 mg, 0.344mmol) according to the general procedure of Example 1.

HPLC purity: 98.3% (254 nm)

Mass spectroscopy: (ESI+ve) 292.2 (M+H)⁺

¹H NMR: (400 MHz, d6-DMSO) δ: 2.77 (s, 6H), 6.58 (m, 1H), 6.67 (m, 2H),7.09 (m, 1H), 7.32 (bs, 2H), 7.34 (m, 2H), 7.40 (m, 3H).

(xxviii) N-[3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]acetamide

N-[3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]acetamide (59 mg, 62%)was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299mmol) and 3-acetamidophenylboronic acid (61.5 mg, 0.344 mmol) accordingto the general procedure of Example 1.

HPLC purity: 100% (254 nm)

Mass spectroscopy: (ESI+ve) 306.2 (M+H)⁺

¹H NMR: (400 MHz, d6-DMSO) δ: 1.95 (s, 3H), 6.70 (m, 1H), 7.07 (m, 1H),7.25-7.35 (m, 6H), 7.52 (m, 2H), 7.64 (m, 1H), 9.89 (s, 1H).

(xxix)N-[3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]methanesulfonamide

N-[3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]methanesulfonamide (42mg, 41%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75mg, 0.299 mmol) andN-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide(102 mg, 0.344 mmol) according to the general procedure of Example 1.

HPLC purity: 100% (254 nm)

Mass spectroscopy: (ESI+ve) 342.2 (M+H)⁺

¹H NMR: (400 MHz, d6-DMSO) δ: 2.79 (s, 3H), 7.02 (m, 1H), 7.36 (m, 1H),7.26 (m, 2H), 7.35-7.48 (m, 7H), 9.78 (s, 1H).

(xxx) 6-(3-Chlorophenyl)-5(2,4-difluorophenyl)-1,2,4-triazin-3-amine

6-(3-Chlorophenyl)-5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine (23 mg,15%) was prepared from6-bromo-5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine (0.13 g, 0.40 mmol)and 3-chlorophenylboronic acid (0.07 g, 0.40 mmol) according to thegeneral procedure of Example 1.

HPLC purity: 98.7% (260 nm)

Mass spectroscopy: (ESI+ve) 318.9 [M+H]⁺, 317.1 [M−H]⁻.

¹H NMR: (400 MHz, CDCl₃) δ: 5.64 (s, 2H), 6.75 (m, 1H), 7.01 (m, 1H),7.20 (m, 2H), 7.32 (m, 1H), 7.48 (s, 1H), 7.54 (m, 1H).

(xxxi) 6-(3-Chlorophenyl)-5-(3-methoxyphenyl)-1,2,4-triazin-3-amine

6-(3-Chlorophenyl)-5-(3-methoxyphenyl)-1,2,4-triazin-3-amine (18 mg 9%)was prepared from 6-bromo-5-(3-methoxyphenyl)-1,2,4-triazin-3-amine(0.18 g, 0.60 mmol) and 3-chlorophenylboronic acid (0.10 g, 0.60 mmol)according to the general procedure of Example 1.

HPLC purity: 88% (258 nm)

Mass spectroscopy: (ESI+ve) 313.0 [M+H]⁺, 311.1 [M−H]⁻.

¹H NMR: (400 MHz, CDCl₃) δ: 3.72 (s, 3H), 6.53 (s, 2H), 7.04 (m, 3H),7.23-7.30 (m, 3H), 7.37 (d, 1H), 7.49 (s, 1H).

(xxxii) 6-(3-Chlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine

6-(3-Chlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (65.0 mg,19%) was prepared from 6-bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine(0.30 g, 1.11 mmol) and 3-chlorophenylboronic acid (0.19 g, 1.23 mmol)according to the general procedure of Example 1.

HPLC purity: 98% (261 nm)

Mass spectroscopy: (ESI+ve) 300.9 [M+H]⁺.

¹H NMR: (400 MHz, CDCl₃) δ: 5.47 (s, 2H), 7.03 (m, 2H), 7.19-7.26 (m,3H), 7.33 (m, 1H), 7.47 (m, 2H), 7.53 (m, 1H).

(xxxiii) 6-(2-Methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(2-Methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (108 mg, 48%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol)and 2-methoxyphenyl boronic acid (0.137 g, 0.90 mmol) according to thegeneral procedure of Example 1.

HPLC purity: 99.28% (223 nm)

Mass spectroscopy: (ESI+ve) 278.9 [M+H]⁺.

¹H NMR: (400 MHz, CDCl₃) δ: 3.20 (s, 3H), 5.49 (s, 2H), 6.70 (t, 1H)7.10 (m, 2H), 7.26 (m, 1H), 7.32-7.39 (m, 2H), 7.43 (m, 2H), 7.64 (dd,1H).

(xxxiv) 6-(3-trifluoromethoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(3-trifluoromethoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (170 mg,25%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g,1.99 mmol) and 3-(trifluoromethoxy)phenyl boronic acid (0.44 g, 2.13mmol) according to the general procedure of Example 1.

HPLC purity: 99% (262 nm)

Mass spectroscopy: (ESI+ve) 332.9 [M+H]⁺

¹H NMR: (400 MHz, CDCl3) δ: 5.46 (s, 2H), 7.19 (m, 1H), 7.25 (m, 1H)7.36 (m, 3H), 7.43 (t, 4H).

(xxxv) 6-(1-benzofuran-5-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(1-benzofuran-5-yl)-5-phenyl-1,2,4-triazin-3-amine (225 mg, 47%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol)and benzofuran-5 boronic acid (0.32 g, 1.99 mmol) according to thegeneral procedure of Example 1.

HPLC purity: 99.61% (245 nm)

Mass spectroscopy: (ESI+ve) 288.9 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 6.92 (m, 1H), 7.20 (m, 1H), 7.27 (m, 2H),7.36 (m, 5H), 7.52 (d, 1H), 7.66 (d, 1H), 7.98 (d, 1H).

(xxxvi) 5-phenyl-6-[3-(propan-2-yl)phenyl]-1,2,4-triazin-3-amine

5-phenyl-6-[3-(propan-2-yl)phenyl]-1,2,4-triazin-3-amine (110 mg, 33%)was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.3 g, 1.19mmol) and 3-isopropyl phenyl boronic acid (0.215 g, 1.31 mmol) accordingto the general procedure of Example 1.

HPLC purity: 99.78% (262 nm)

Mass spectroscopy: (ESI+ve) 291.0 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 1.09 (d, 6H), 2.79 (m, 1H), 5.48 (bs, 2H),7.19 (m, 2H), 7.31 (m, 4H), 7.44 (m, 3H).

(xxxvii) 6-(3,5-dichlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine

6-(3,5-dichlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (0.11 g,17.6%) was prepared from6-Bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (0.5 g, 1.18 mmol) and3,5-dichloro phenylboronic acid (0.47 mg, 2.4 mmol) according to thegeneral procedure of Example 1.

HPLC purity: 97.46% (225 nm)

Mass spectroscopy: (ESI+ve) 334.9 [M]⁺.

¹H NMR: (400 MHz, DMSO) δ: 7.24 (m, 2H), 7.34 (m, 2H), 7.45 (m, 2H),7.58 (m, 3H).

(xxxviii)4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-(propan-2-yloxy)phenol

4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-(propan-2-yloxy)phenol (0.450g, 18%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (1.9 g,7.52 mmol) and 3-isopropoxy-4-hydroxyphenylboronic acid pinacol ester(2.5 g, 9.02 mmol) according to the general procedure of Example 1.

HPLC purity: 94.14% (290 nm)

Mass spectroscopy: (ESI+ve) 323.1 [M+H]⁺ (ESI−ve) 321.1 [M+H]⁺.

¹H NMR: (400 MHz, DMSO) δ: 1.04 (d, 6H), 4.20 (m, 1H), 6.68 (m, 1H),6.70 (m, 1H), 6.84 (m, 1H), 7.26 (bs, 2H), 7.32-7.44 (m, 5H), 9.01 (s,1H).

The compounds in the following table were prepared using the generalprocedure outlined for Example 1, by reacting the corresponding startingmaterials at 140° C. for 1 hour.

No. Product (yield) Prepared From LCMS NMR (xxxix) 6-(3,5-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: bis(trifluoromethyl)phe-1,2,4-triazin-3-amine spectroscopy: m/z 7.35-7.43 (m, 4H),nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 385.3 (M + H)⁺ 7.44-7.50 (m,1H), triazin-3-amine (50.2 and 3,5- (ES⁺); 383.5 (M − H)⁻ 7.68 (s, 2H),7.94 (s, mg, 0.131 mmol, bis(trifluoromethyl)phe- (ES⁻), at 4.89 min,2H), 8.06 (s, 1H). 36.4%) nylboronic acid (106 100% (method B). mg,0.412 mmol) (xl) 4-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz,DMSO) δ: 1,2,4-triazin-6-yl)-2- 1,2,4-triazin-3-amine spectroscopy: m/z3.55 (s, 3H), 6.65- methoxyphenol (42.5 (90 mg, 0.358 mmol) 295.2 (M +H)⁺ 6.76 (m, 2H), 6.85 (d, mg, 0.139 mmol, and -methoxy-4- (ES⁺); 293.4(M − H)⁻ J 1.8, 1H), 7.28 (s, 38.7%) (4,4,5,5-tetramethyl- (ES⁻), at2.70 min, 2H), 7.33-7.45 (m, 1,3,2-dioxaborolan-2- 96.0% (method B).5H), 9.18 (s, 1H). yl)phenol (103 mg, 0.412 mmol) (xli)4-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:1,2,4-triazin-6-yl)- 1,2,4-triazin-3-amine spectroscopy: m/z 2.06 (s,6H), 6.87 (s, 2,6-dimethylphenol (90 mg, 0.358 mmol) 293.2 (M + H)⁺ 2H),7.31-7.64 (m, (41.3 mg, 0.141 and 2,6-dimethyl-4- (ES⁺); 291.4 (M − H)⁻7H), 8.46 (s, 1H). mmol, 39.4%) (4,4,5,5-tetramethyl- (ES⁻), at 3.57min, 1,3,2-dioxaborolan-2- 100% (method B). yl)phenol (102 mg, 0.412mmol) (xlii) 4-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO)δ: 1,2,4-triazin-6-yl)-2- 1,2,4-triazin-3-amine spectroscopy: m/z 6.87(d, J 8.4, 1H), chlorophenol (26.8 (90 mg, 0.358 mmol) (Cl) 299.2/301.27.03 (dd, J 8.4, 2.2, mg, 0.085 mmol, and 3-chloro-4- (M + H)⁺ (ES⁺);1H), 7.31 (d, J 2.2, 23.78%) hydroxyphenylboronic 297.4/299.4 (M − H)⁻1H), 7.33-7.47 (m, acid (64.9 mg, (ES⁻), at 2.15 min, 7H), 10.38 (s,1H). 0.376 mmol) 97.1% (method B). (xliii) 6-(2-chloropyridin-4-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: yl)-5-phenyl-1,2,4-1,2,4-triazin-3-amine spectroscopy: m/z 7.28 (dd, J 5.2, 1.5,triazin-3-amine (22.5 (90 mg, 0.358 mmol) (Cl) 284.1/286.1 1H),7.38-7.53 (m, mg, 0.079 mmol, and 2-chloropyridin- (M + H)⁺ (ES⁺); 6H),7.74 (s, 2H), 22.12%) 4-ylboronic acid 282.3/284.3 (M − H)⁻ 8.33 (dd, J5.2, 0.6, (59.2 mg, 0.376 (ES⁻), at 3.55 min, 1H). mmol) 100% (methodB). (xliv) 6-(3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:(methylsulfonyl)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 3.10 (s,3H), 7.33- nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 327.2 (M + H)⁺ 7.48(m, 5H), 7.50- triazin-3-amine (78.8 and 3- (ES⁺); 325.4 (M − H)⁻ 7.68(m, 4H), 7.83- mg, 0.241 mmol, (methylsulfonyl)phe- (ES⁻), at 3.12 min,7.91 (m, 2H). 67.4%) nylboronic acid (82 100% (method B). mg, 0.412mmol) (xlv) 6-(3,5-dichloro-4- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:methoxyphenyl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 3.83 (s, 3H),7.37- phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) (2Cl) 7.50 (m, 7H), 7.55(s, 3-amine (52 mg, and 3,5-dichloro-4- 347.2/349.2/351.2 2H). 0.147mmol, 41.1%) methoxyphenylboronic (M + H)⁺ (ES⁺); acid (83 mg, 0.376345.3/347.3/349.4 mmol) (M − H)⁻ (ES⁻), at 4.57 min, 91.0% (method B).(xlvi) 6-(4-methoxy-3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:(trifluoromethyl)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 3.88 (s,3H), 7.21 (d, nyl)-5-phenyl-1,2,4- (75 mg, 0.299 mmol) 347.2 (M + H)⁺ J8.6, 1H), 7.33- triazin-3-amine (53.4 and 4-methoxy-3- (ES⁺); 345.4 (M −H)⁻ 7.50 (m, 7H), 7.51- mg, 0.154 mmol, (trifluoromethyl)phe- (ES⁻), at4.25 min, 7.59 (m, 2H). 51.6%) nylboronic acid (76 100% (method B). mg,0.344 mmol) (xlvii) 6-(3-chloro-5- 6-bromo-5-phenyl- Mass (400 MHz,DMSO) δ: (dimethylamino)phe- 1,2,4-triazin-3-amine spectroscopy: m/z2.75 (s, 6H), 6.47- nyl)-5-phenyl-1,2.4- (90 mg, 0.358 mmol) (Cl)326.3/328.2 6.53 (m, 1H), 6.61- triazin-3-amine (68.3 and 3-chloro-N,N-(M + H)⁺ (ES⁺): 6.68 (m, 2H), 7.30- mg, 0.204 mmol, dimethyl-5-(4,4,5,5-324.4/326.4 (M − H)⁻ 7.54 (m, 7H). 57.0%) tetramethyl-1,3,2- (ES⁻), at4.53 min, dioxaborolan-2- 100% (method B). yl)aniline (106 mg, 0.376mmol) (xlviii) 3-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz,DMSO) δ: 1,2,4-triazin-6-yl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z7.36-7.42 (m, 4H), (trifluoromethyl)benzo- (90 mg, 0.358 mmol) 342.9(M + H)⁺ 7.43-7.51 (m, 1H), nitrile (47.5 mg, and 3-(4,4,5,5- (ES⁺);341.0 (M − H)⁻ 7.69 (s, 2H), 7.90 (s, 0.137 mmol, 38.2%)tetramethyl-1,3,2- (ES⁻), at 4.25 min, 1H), 8.09(s, 1H),dioxaborolan-2-yl)-5- 98.4% (method B). 8.31 (s, 1H).(trifluoromethyl)benzo- nitrile (122 mg, 0.412 mmol) (xlix)4-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:1,2,4-triazin-6-yl)- 1,2,4-triazin-3-amine spectroseopy: m/z 2.37 (s,6H), 7.22 (s, 2,6- (90 mg, 0.358 mmol) 302.2 (M + H)⁺ 2H), 7.35-7.42 (m,dimethylbenzonitrile and 2,6-dimethyl-4- (ES⁺); 300.4 (M − H)⁻ 4H),7.43-7.49 (m, (72.4 mg, 0.233 (4,4,5,5-tetramethyl- (ES⁻), at 4.14 min,1H), 7.57 (s, 2H). mmol, 65.0%) 1,3,2-dioxaborolan-2- 100% (method B).yl)benzonitrile (106 mg, 0.412 mmol) (l) 6-(3-chloro-5-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe-1,2,4-triazin-3-amine spectroscopy: m/z 7.35-7.43 (m, 4H),nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 351.9 (M + H)⁺ 7.44-7.49 (m,1H), triazin-3-amine (42.5 and 2-(3-chloro-5- (ES⁺); 350.0 (M − H)⁻ 7.55(s, 1H), 7.63 (s, mg, 0.117 mmol, (trifluoromethyl)phe- (ES⁻), at 4.80min, 2H), 7.72 (s, 1H), 32.6%) nyl)-4,4,5,5- 96.4% (method B). 7.82 (s,1H). tetramethyl-1,3,2- dioxaborolane (115 mg, 0.376 mmol) (li)6-(3-chloro-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:methylphenyl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 2.24 (s, 3H),7.07- phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) (Cl) 297.1/299.3 7.12(m, 1H), 7.13- 3-amine (65.1 mg, and 3-chloro-5- (M + H)⁺ (ES⁺); 7.17(m, 1H), 7.21- 0.219 mmol, 61.2%) methylphenylboronic 295.3/297.3 (M −H)⁻ 7.25 (m, 1H), 7.33- acid (64.1 mg, 0.376 (ES⁻), at 4.55 min, 7.57(m, 7H). mmol) 100% (method B). (lii) 6-(3-(methylthio)-5- from6-bromo-5- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe-phenyl-1,2,4-triazin- spectroscopy: m/z 2.33 (s, 3H), 7.35-nyl)-5-phenyl-1,2,4- 3-amine (90 mg, 363.2 (M + H)⁺ 7.43 (m, 6H), 7.43-triazin-3-amine (66 0.358 mmol) and 3- (ES⁺); 361.4 (M − H)⁻ 7.47 (m,1H), 7.57 (s, mg, 0.181 mmol, (methylthio)-5- (ES⁻), at 4.75 min, 2H),7.49 (s, 1H). 50.5%) (trifluoromethyl)phe- 99.4% (method B). nylboronicacid (97 mg, 0.412 mmol) (liii) 6-(3-methoxy-5- 6-bromo-5-phenyl- Mass(400 MHz, DMSO) δ: (trifluoromethyl)phe- 1,2,4-triazin-3-aminespectroscopy: m/z 3.71 (s, 3H), 7.14- nyl)-5-phenyl-1,2,4- (90 mg, 0.358mmol) 347.2 (M + H)⁺ 7.22 (m, 3H), 7.35- triazin-3-amine (62.9 and3-methoxy-5- (ES⁺); 345.4 (M − H)⁻ 7.42 (m, 4H), 7.42- mg, 0.179 mmol,(trifluoromethyl)phe- (ES⁻), at 4.52 min, 7.47 (m, 1H), 7.55 (s, 49.9%)nylboronic acid (91 99.5% (method B). 2H). mg, 0.412 mmol) (liv)6-(3-ethoxy-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:(trifluoromethyl)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 1.23 (t, J7.0, 3H), nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 361.2 (M + H)⁺ 3.97(q, J 7.0, 2H), triazin-3-amine (76.4 and 3-ethoxy-5- (ES⁺); 359.5 (M −H)⁻ 7.12-7.15 (m, 1H), mg, 0.211 mmol, (trifluoromethyl)phe- (ES⁻), at4.74 min, 7.15-7.17 (m, 1H), 58.8%) nylboronic acid (96 99.4% (methodB). 7.18-7.21 (m, 1H), mg, 0.412 mmol) 7.34-7.48 (m, 5H), 7.54 (s, 2H).(lv) 6-(3-tert-butyl-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:methylphenyl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 1.03 (s, 9H),2.31 (s, phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) 319.5 (M + H)⁺ 3H),6.80-6.85 (m, 3-amine (80 mg, and with 3-tert-butyl- (ES⁺); 317.5 (M −H)⁻ 1H), 7.11-7.15 (m, 0.249 mmol, 69.5%) 5- (ES⁻), at 4.99 min, 1H),7.24-7.28 (m, methylphenylboronic 99.1% (method B). 1H), 7.30-7.44 (m,acid (79 mg, 0.412 7H). mmol) (lvi) 6-(2-chloro-6- 6-bromo-5-phenyl-Mass (400 MHz, DMSO) δ: methylpyridin-4-yl)-5- 1,2,4-triazin-3-aminespectroscopy: m/z 2.39 (s, 3H), 7.08- phenyl-1,2,4-triazin- (90 mg,0.358 mmol) (Cl) 298.1/300.1 7.13 (m, 1H), 7.24- 3-amine (52.5 mg, and2-chloro-6- (M + H)⁺ (ES⁺): 7.30 (m, 1H), 7.39- 0.170 mmol, 47.3%)methyl-4-(4,4,5,5- 296.3/298.3 (M − H)⁻ 7.45 (m, 4H), 7.46-tetramethyl-1,3,2- (ES⁻), at 3.73 min, 7.53 (m, 1H), 7.71 (s,dioxaborolan-2- 99.6% (method B). 2H). yl)pyridine (100 mg, 0.394 mmol)(lvii) 4-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:1,2,4-triazin-6-yl)-2- 1,2,4-triazin-3-amine spectroscopy: m/z 7.36-7.44(m, 5H), chlorobenzonitrile (90 mg, 0.358 mmol) (Cl) 308.1/310.17.44-7.50 (m, 1H), (29 mg, 0.092 mmol, and 3-chloro-4- (M + H)⁺ (ES⁺);7.69 (s, 2H), 7.73 (d, 25.7%) cyanophenylboronic 306.3/308.3 (M − H)⁻ J1.3, 1H), 7.91 (d, J acid (71.5 mg, 0.394 (ES⁻), at 4.02 min, 8.2, 1H).mmol) 97.9% (method B). (lviii) 6-(3-ethylphenyl)-5- 6-bromo-5-phenyl-Mass (400 MHz, DMSO) δ: phenyl-1,2,4-triazin- 1,2,4-triazin-3-aminespectroscopy: m/z 1.03 (t, J 7.6, 3H), 3-amine (70 mg, (90 mg, 0.358mmol) 277.2 (M + H)⁺ 2.51 (q, J 7.6, 2H), 0.252 mmol, 70.3%) and 3-(ES⁺); 275.4 (M − H)⁻ 7.12-7.18 (m, 3H), ethylphenylboronic (ES⁻), at4.49 min, 7.20-7.26 (m, 1H), acid (61.8 mg, 0.412 99.5% (method B).7.31-7.45 (m, 7H). mmol) (lix) 6-(2-methoxy-6- 6-bromo-5-phenyl- Mass(400 MHz, DMSO) δ: (trifluoromethyl)pyridin- 1,2,4-triazin-3-aminespectroscopy: m/z 3.86 (s, 3H), 7.00- 4-yl)-5-phenyl- (90 mg, 0.358mmol) 348.2 (M + H)⁺ 7.04 (m, 1H), 7.34 (d, 1,2,4-triazin-3-amine and2-methoxy-4- (ES⁺); 346.4 (M − H)⁻ J 1.1, 1H), 7.38- (61.6 mg, 0.176(4,4,5,5-tetramethyl- (ES⁻), at 4.47 min, 7.46 (m, 4H), 7.46- mmol,49.2%) 1,3,2-dioxaborolan-2- 99.4% (method B). 7.52 (m, 1H), 7.75 (s,yl)-6- 2H). (trifluoromethyl)pyri- dine (125 mg, 0.412 mmol) (lx)6-(3-methyl-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:(trifluoromethoxy)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 2.32 (s,3H), 6.85- nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 347.2 (M + H)⁺ 6.91(m, 1H), 7.12- triazin-3-amine (41 and 4,4,5,5- (ES⁺); 345.4 (M − H)⁻7.18 (m, 1H), 7.32- mg, 0.116 mmol, tetramethyl-2-(3- (ES⁻), at 4.72min, 7.41 (m, 5H), 7.41- 32.3%) methyl-5- 97.7% (method B). 7.47 (m,1H), 7.51 (s, (trifluoromethoxy)phe- 2H). nyl)-1,3,2- dioxaborolane (125mg, 0.412 mmol) (lxi) 6-(3-(1,3-dioxolan-2- from 6-bromo-5- Mass (400MHz, DMSO) δ: yl)-5- phenyl-1,2,4-triazin- spectroscopy: m/z 3.92 (s,4H), 5.81 (s, (trifluoromethyl)phe- 3-amine (90 mg, 389.3 (M + H)⁺ 1H),7.34-7.41 (m, nyl)-5-phenyl-1,2,4- 0.358 mmol) and 3- (ES⁺); 387.5 (M −H)⁻ 4H), 7.41-7.48 (m, triazin-3-amine (76 (1,3-dioxolan-2-yl)-5- (ES⁻),at 4.32 min, 1H), 7.57 (s, 2H), mg, 0.194 mmol, (trifluoromethyl)phe-95.3% (method B). 7.60 (s, 1H), 7.68 (s, 54.2%) nylboronic acid (1081H), 7.73 (s, 1H). mg, 0.412 mmol) (lxii) 5-phenyl-6-(3-(2,2,2-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: trifluoroethoxy)phe-1,2,4-triazin-3-amine spectroscopy: m/z 4.69 (q, J 8.9, 2H),nyl)-1,2,4-triazin-3- (90 mg, 0.358 mmol) 347.2 (M + H)⁺ 6.87-6.93 (m,1H), amine (86 mg, 0.246 and 3-(2,2,2- (ES⁺); 345.4 (M − H)⁻ 7.02 (ddd,J 8.3, 2.7, mmol, 68.6%) trifluoroethoxy)phenyl- (ES⁻), at 4.30 min,0.8, 1H), 7.07-7.12 boronic acid (91 mg, 99.0% (method B). (m, 1H), 7.25(t, J 0.412 mmol) 8.0, 1H), 7.31-7.52 (m, 7H). (lxiii) 6-(3-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (methoxymethyl)phe-1,2,4-triazin-3-amine spectroscopy: m/z 3.16 (s, 3H), 4.35 (s,nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 293.0 (M + H)⁺ 2H), 7.16-7.22(m, triazin-3-amine (76 and 3- (ES⁺); 291.3 (M − H)⁻ 1H), 7.25-7.30 (m,mg, 0.256 mmol, (methoxymethyl)phe- (ES⁻), at 3.85 min, 2H), 7.30-7.37(m, 71.4%) nylboronic acid (68.4 98.5% (method B). 3H), 7.36-7.49 (m,mg, 0.412 mmol) 5H). (lxiv) 5-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass(400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)-1- 1,2,4-triazin-3-aminespectroscopy: m/z 3.44 (s, 3H), 6.23 (d, methylpyridin-2(1H)- (90 mg,0.358 mmol) 280.0 (M + H)⁺ J 9.4, 1H), 7.03 (dd, J one (50 mg, 0.177 and1-methyl-5- (ES⁺); 278.2 (M − H)⁻ 9.4, 2.6, 1H), 7.33- mmol, 49.2%)(4,4,5,5-tetramethyl- (ES⁻), at 2.73 min, 7.50 (m, 5H), 7.51-1,3,2-dioxaborolan-2- 98.6% (method B). 7.57 (m, 2H), 7.97 (d,yl)pyridin-2(1H)-one J 2.5, 1H). (97 mg, 0.412 mmol) (lxv)6-(3-methyl-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:(trifluoromethyl)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 2.33 (s,3H), 7.32 (s, nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 331.1 (M + H)⁺1H), 7.34-7.41 (m, triazin-3-amine (79 and 3-methyl-5- (ES⁺); 329.3 (M −H)⁻ 4H), 7.41-7.47 (m, mg, 0.239 mmol, (trifluoromethyl)phe- (ES⁻), at4.62 min, 1H), 7.48-7.60 (m, 66.6%) nylboronic acid (84 99.8% (methodB). 4H). mg, 0.412 mmol) (lxvi) 6-(2-methoxypyridin- 6-bromo-5-phenyl-Mass (400 MHz, DMSO) δ: 4-yl)-5-phenyl-1,2,4- 1,2,4-triazin-3-aiminespectroscopy: m/z 3.81 (s, 3H), 6.75 triazin-3-amine (39 (90 mg, 0.358mmol) 280.1 (M + H)⁺ (dd, J 1.4, 0.7, 1H), mg, 39%) and 2-methoxy-4-(ES⁺); 278.4 (M − H)⁻ 6.88 (dd, J 5.3, 1.5, (4,4,5,5-tetramethyl- (ES⁻),at 3.60 min, 1H), 7.34-7.51 (m, 1,3,2-dioxaborolan-2- 99.4% (method B).5H), 7.61 (s, 2H), yl)pyridine (97 mg, 8.08 (dd, J 5.3, 0.7, 0.412 mmol)1H). (lxvii) 1-(3-(3-amino-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:phenyl-1,2,4-triazin- 1,2,4-triazin-3-amine spectroscopy; m/z 2.46 (s,3H), 7.32- 6-yl)phenyl)ethanone (90 mg, 0.358 mmol) 291.1 (M + H)⁺ 7.52(m, 8H), 7.52- (71 mg, 0.243 mmol, and 3- (ES⁺); 289.3 (M − H)⁻ 7.57 (m,1H), 7.87- 67.8%) acetylphenylboronic (ES⁻), at 3.62 min, 7.93 (m, 1H),7.93- acid (67.6 mg, 0.412 99.4% (method B). 7.98 (m, 1H). mmol)(lxviii) 4-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:1,2,4-triazin-6- 1,2,4-triazin-3-amine spectroscopy: m/z 7.31-7.46 (m,8H), yl)benzamide (73 (90 mg, 0.358 mmol) 292.2 (M + H)⁺ 7.48 (s, 2H),7.81 (d, mg, 0.243 mmol, and 4- (ES⁺); 290.4 (M − H)⁻ J 8.5, 2H), 7.98(s, 67.7%) carbamoylphenylbo- (ES⁻), at 2.93 min, 1H). ronic acid (68.0mg, 96.9% (method B). 0.412 mmol) (lxix) 6-(4-fluoro-3-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe-1,2,4-triazin-3-amine spectroscopy: m/z 7.32-7.51 (m, 6H),nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 335.2 (M + H)⁺ 7.55 (s, 2H),7.63- triazin-3-amine (83 and 2-(4-fluoro-3- (ES⁺); 333.4 (M − H)⁻ 7.68(m, 1H), 7.70 mg, 0.244 mmol, (trifluoromethyl)phe- (ES⁻), at 4.42 min,(dd, J 7.0, 2.1, 1H). 68.0%) nyl)-4,4,5,5- 98.2% (method B).tetramethyl-1,3,2- dioxaborolane (120 mg, 0.412 mmol) (lxx)6-(4-fluoro-3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:methylphenyl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 2.19 (s, 3H),7.00- phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) 281.1 (M + H)⁺ 7.09 (m,2H), 7.32- 3-amine (72 mg, and 4-fluoro-3- (ES⁺); 279.3 (M − H)⁻ 7.46(m, 8H). 0.257 mmol, 71.7%) methylphenylboronic (ES⁻), at 4.32 min, acid(63.5 mg, 0.412 100% (method B). mmol) (lxxi) 6-(3-bromo-5-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: chlorophenyl)-5-1,2,4-triazin-3-amine spectroscopy: m/z 7.36-7.38 (m, 1H),phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) (Br) 7.39-7.44 (m, 4H),3-amine (30 mg, and 2-(3-bromo-5- 361.2/363.1/365.1 7.44-7.50 (m, 2H),0.083 mmol, 23.14%) chlorophenyl)- (M + H)⁺ (ES⁺); 7.59 (s, 2H), 7.69(t, J 4,4,5,5-tetramethyl- 359.3/361.3/363.3 1.9, 1H).1,3,2-dioxaborolane (M − H)⁻ (ES⁻), at (116 mg, 0.366 5.07 min, 100%mmol) (method B). (lxxii) 6-(naphthalen-2-yl)- from 6-bromo-5- Mass (400MHz, DMSO) δ: 5-phenyl-1,2,4- phenyl-1,2,4-triazin- spectroscopy: m/z7.28-7.36 (m, 3H), triazin-3-amine (83 3-amine (90 mg, 299.2 (M + H)⁺7.37-7.48 (m, 5H), mg, 0.278 mmol, 77%) 0.358 mmol) and (ES⁺), at 4.67min, 7.48-7.56 (m, 2H), naphthalen-2- 99.8% (method B). 7.81 (d, J 8.7,1H), ylboronic acid (70.9 7.83-7.92 (m, 2H), mg, 0.412 mmol) 8.02 (s,1H). (lxxiii) 5-phenyl-6-m-tolyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO)δ: 1,2,4-triazin-3-amine 1,2,4-triazin-3-amine spectroscopy: m/z 2.26(s, 3H), 6.97- (73.4 mg, 0.278 (90 mg, 0.358 mmol) 263.2 (M + H)⁺ 7.02(m, 1H), 7.11- mmol, 78%) and m-tolylboronic (ES⁺); 261.3 (M − H)⁻ 7.20(m, 2H), 7.26 (s, acid (56.0 mg, 0.412 (ES⁻), at 4.43 min, 1H),7.30-7.45 (m, mmol) 99.4% (method B). 7H). (lxxiv) 5-phenyl-6-(pyridin-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 4-yl)-1,2,4-triazin-3-1,2,4-triazin-3-amine spectroscopy: m/z 7.32 (dd, J 4.4, 1.7, amine (16mg, 0.064 (90 mg, 0.358 mmol) 250.2 (M + H)⁺ 2H), 7.34-7.43 (m, mmol,17.78%) and pyridin-4- (ES⁺); 248.3 (M − H)⁻ 4H), 7.43-7.50 (m,ylboronic acid (50.7 (ES⁻), at 3.34 min, 1H), 7.63 (s, 2H), mg, 0.412mmol) 99.3% (method B). 8.51 (dd, J 4.5, 1.6, 2H). (lxxv)4-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:1,2,4-triazin-6- 1,2,4-triazin-3-amine spectroscopy: m/z 6.69 (d, J 8.7,2H), yl)phenol (21 mg, (90 mg, 0.358 mmol) 265.1 (M + H)⁺ 7.12 (d, J8.6, 2H), 0.078 mmol, 21.81%) and 4-(4,4,5,5- (ES⁺); 263.4 (M − H)⁻ 7.26(s, 2H), 7.31- tetramethyl-1,3,2- (ES⁻), at 2.77 min, 7.44 (m, 5H), 9.59(s, dioxaborolan-2- 98.4% (method B). 1H). yl)phenol (91 mg, 0.412 mmol)(lxxvi) 6-(2,6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:dimethoxypyridin-4- 1,2,4-triazin-3-amine spectroscopy: m/z 3.79 (s,6H), 6.29 (s, yl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 310.2 (M + H)⁺2H), 7.35-7.49 (m, triazin-3-amine (61 and 2,6-dimethoxy-4- (ES⁺); 308.4(M − H)⁻ 5H), 7.58 (s, 2H). mg, 0.196 mmol, (4,4,5,5-tetramethyl- (ES⁻),at 4.27 min, 54.8%) 1,3,2-dioxaborolan-2- 99.6% (method B). yl)pyridine(109 mg, 0.412 mmol) (lxxvii) 6-(2,6- from 6-bromo-5- Mass (400 MHz,DMSO) δ: dimethylpyridin-4-yl)- phenyl-1,2,4-triazin- spectroscopy: m/z2.33 (s, 6H), 6.97 (s, 5-phenyl-1,2,4- 3-amine (90 mg, 278.2 (M + H)⁺2H), 7.35-7.43 (m, triazin-3-amine (44 0.358 mmol) and 2,6- (ES⁺); 276.4(M − H)⁻ 4H), 7.43-7.50 (m, mg, 0.154 mmol, dimethyl-4-(4,4,5,5- (ES⁻),at 3.77 min, 1H), 7.58 (s, 2H). 42.8%) tetramethyl-1,3,2- 96.8% (methodB). dioxaborolan-2- yl)pyridine (96 mg, 0.412 mmol) (lxxviii)5-phenyl-6-(2- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:(trifluoromethyl)pyridin- 1,2,4-triazin-3-amine spectroscopy: m/z7.37-7.45 (m, 4H), 4-yl)-1,2,4-triazin- (90 mg, 0.358 mmol) 318.2 (M +H)⁺ 7.46-7.53 (m, 1H), 3-amine (31 mg, and 2- (ES⁺); 316.4 (M − H)⁻ 7.63(dd, J 5.0, 1.2, 0.098 mmol, 27.3%) (trifluoromethyl)pyridin- (ES⁻), at4.03 min, 1H), 7.75 (s, 1H), 4-ylboronic acid 100% (method B). 7.77 (s,2H), 8.70 (d, (79 mg, 0.412 mmol) J 5.1, 1H). (lxxix) 6-(2-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: cyclopropylpyridin-4-1,2,4-triazin-3-amine spectroscopy: m/z 0.76-0.83 (m, 2H),yl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 290.1 (M + H)⁺ 0.87-0.93 (m,2H), triazin-3-amine (61 and 2-cyclopropyl-4- (ES⁺); 288.4 (M − H)⁻1.96-2.06 (m, 1H), mg, 0.206 mmol, (4,4,5,5-tetramethyl- (ES⁻), at 3.92min, 6.97 (dd, J 5.1, 1.7, 57.3%) 1,3,2-dioxaborolan-2- 97.5% (methodB). 1H), 7.25 (dd, J 1.6, yl)pyridine (101 mg, 0.8, 1H), 7.35-7.44 0.412mmol) (m, 4H), 7.44-7.51 (m, 1H), 7.60 (s, 2H), 8.28 (dd, J 5.1, 0.6,1H). (lxxx) 5-phenyl-6-(2,2,6,6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO)δ: tetramethyl-3,6- 1,2,4-triazin-3-amine spectroscopy: m/z 1.01 (s,6H), 1.16 (s, dihydro-2H-pyran-4- (90 mg, 0.358 mmol) 311.2 (M + H)⁺6H), 2.28 (d, J 1.3, yl)-1,2,4-triazin-3- and 4,4,5,5- (ES⁺); 309.4 (M −H)⁻ 2H), 5.46 (t, J 1.4, amine (85 mg, 0.269 tetramethyl-2- (ES⁻), at4.40 min, 1H), 7.29 (s, 2H), mmol, 75%) (2,2,6,6-tetramethyl- 98.2%(method B). 7.43-7.50 (m, 3H), 3,6-dihydro-2H- 7.56-7.61 (m, 2H).pyran-4-yl)-1,3,2- dioxaborolane (110 mg, 0.412 mmol) (lxxxi)6-(5-chloro-2-fluoro- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:3-methylphenyl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 2.07 (d, J1.9, 3H), phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) (Cl) 315.8/317.87.33-7.47 (m, 6H), 3-amine (10 mg, and 5-chloro-2- (M + H)⁺ (ES⁺), at7.50 (dd, J 5.9, 2.8, 0.031 mmol, 8.64%) fluoro-3- 4.67 min, 97.5% 1H),7.60 (s, 2H). methylphenylboronic (method B). acid (78 mg, 0.412 mmol)(lxxxii) 6-(2,6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:dichloropyridin-4-yl)- 1,2,4-triazin-3-amine spectroscopy: m/z 7.41-7.48(m, 6H), 5-phenyl-1,2,4- (250 mg, 0.996 (2 Cl) 7.48-7.55 (m, 1H),triazin-3-amine (7 mmol) and 2,6- 318.0/320.1/322.1 7.85 (s, 2H). mg,0.022 mmol, dichloro-4-(4,4,5,5- (M + H)⁺ (ES⁺); 2.205%)tetramethyl-1,3,2- 316.3/318.2/320.2 dioxaborolan-2- (M − H)⁻ (ES⁻), atyl)pyridine (286 mg, 4.34 min, 94.8% 1.045 mmol) (method B). (lxxxiii)6-(3-bromo-5- 6-iodo-5-phenyl- Mass (400 MHz, DMSO) δ:(trifluoromethoxy)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 7.14-7.19(m, 1H), nyl)-5-phenyl-1,2,4- (100 mg, 0.335 (Br) 411.8/413.8 7.36-7.42(m, 4H), triazin-3-amine (23 mmol) and 3-bromo- (M + H)⁺ (ES⁺):7.42-7.49 (m, 1H), mg, 0.055 mmol, 5- 410.0/412.0 (M − H)⁻ 7.57-7.66 (m,2H), 16.47%) (trifluoromethoxy)phe- (ES⁻), at 5.15 min, 7.63-7.66 (m,1H), nylboronic acid (119 98.8% (method B). 7.67-7.70 (m, 1H). mg, 0.419mmol) (lxxxiv) 4-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz,DMSO) δ: 1,2,4-triazin-6-yl)-2- 1,2,4-triazin-3-amine spectroscopy: m/z3.58 (s, 3H), 6.80 (d, chloro-6- (90 mg, 0.358 mmol) (Cl) 329.0/331.1 J2.0, 1H), 6.92 (d, J methoxyphenol (72 and 2-chloro-6- (M + H)⁺ (ES⁺);2.0, 1H), 7.34-7.47 mg, 0.215 mmol, methoxy-4-(4,4,5,5- 327.2/329.0 (M −H)⁻ (m, 7H), 9.62 (s, 1H). 28.4%) tetramethyl-1,3,2- (ES⁻), at 2.61 min,dioxaborolan-2- 98.2% (method B). yl)phenol (248 mg, 0.870 mmol) (lxxxv)6-(3,5-dichloro-4- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:ethoxyphenyl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 1.36 (t, J 7.0,3H), phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) (2 Cl) 361.8/363.9 4.05(q, J 7.0, 2H), 3-amine (81 mg, and 2-(3,5-dichloro- (M + H)⁺ (ES⁺);7.36-7.50 (m, 7H), 0.214 mmol, 59.8%) 4-ethoxyphenyl)- 360.1/362.1 (M −H)⁻ 7.55 (s, 2H). 4,4,5,5-tetramethyl- (ES⁻), at 5.02 min,1,3,2-dioxaborolane 95.6% (method B). (131 mg, 0.412 mmol) (lxxxvi)6-(6-amino-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:(trifluoromethyl)pyridin- 1,2,4-triazin-3-amine spectroscopy: m/z 6.66(s, 2H), 7.32- 3-yl)-5-phenyl- (90 mg, 0.358 mmol) 333.7 (M + H)⁺ 7.50(m, 7H), 7.62- 1,2,4-triazin-3-amine and 5-(4,4,5,5- (ES⁺); 331.8 (M −H)⁻ 7.67 (m, 1H), 8.01- (30 mg, 0.089 mmol, tetramethyl-1,3,2- (ES⁻), at3.80 min, 8.09 (m, 1H). 24.78%) dioxaborolan-2-yl)-3- 98.4% (method B).(trifluoromethyl)pyridin- 2-amine (119 mg, 0.412 mmol) (lxxxvii)4-(3-amino-5-(3- 6-bromo-5-(3- Mass (400 MHz, DMSO) δ:fluorophenyl)-1,2,4- fluorophenyl)-1,2,4- spectroscopy: m/z 2.39 (s,6H), 7.11- triazin-6-yl)-2,6- triazin-3-amine (90 320.9 (M + H)⁺ 7.17(m, 1H), 7.25 (s, dimethylbenzonitrile mg, 0.334 mmol) (ES⁺); 319.1 (M −H)⁻ 2H), 7.26-7.35 (m, (70 mg, 0.219 mmol, and 2,6-dimethyl-4- (ES⁻), at4.37 min, 2H), 7.37-7.44 (m, 65.5%) (4,4,5,5-tetramethyl- 99.9% (methodB). 1H), 7.64 (s, 2H). 1,3,2-dioxaborolan-2- yl)benzonitrile (99 mg,0.385 mmol) (lxxxviii) 6-(3-chloro-5- 6-bromo-5-phenyl- Mass (400 MHz,DMSO) δ: (trifluoromethyl)phe- 1,2,4-triazin-3-amine spectroscopy: m/z7.15-7.21 (m, 1H), nyl)-5-(3- (90 mg, 0.358 mmol) (Cl) 369.8/371.97.25-7.36 (m, 2H), fluorophenyl)-1,2,4- and 2-(3-chloro-5- (M + H)⁺(ES⁺); 7.39-7.46 (m, 1H), triazin-3-amine (54 (trifluoromethyl)phe-368.0/370.0 (M − H)⁻ 7.55-7.60 (m, 1H), mg, 0.141 mmol, nyl)-4,4,5,5-(ES⁻), at 4.99 min, 7.70 (s, 2H), 7.73- 42.1%) tetramethyl-1,3,2- 96.1%(method B). 7.77 (m, 1H), 7.84- dioxaborolane (118 7.88 (m, 1H). mg,0.385 mmol) (lxxxix) 6-(2-chloropyridin-4- 6-bromo-5-phenyl- Mass (400MHz, DMSO) δ: yl)-5-(3- 1,2,4-triazin-3-amine spectroscopy: m/z7.16-7.23 (m, 1H), fluorophenyl)-1,2,4- (90 mg, 0.358 mmol) (Cl)302.8/304.8 7.27-7.38 (m, 3H), triazin-3-amine (28 and 2-chloro-4- (M +H)⁺ (ES⁺); 7.41-7.48 (m, 1H), mg, 0.090 mmol, (4,4,5,5-tetramethyl-301.0/303.0 (M − H)⁻ 7.49 (dd, J 1.5, 0.7, 26.9%) 1,3,2-dioxaborolan-2-(ES⁻), at 3.87 min, 1H), 7.80 (s, 2H), yl)pyridine (92 mg, 97.1% (methodB). 8.35 (dd, J 5.2, 0.7, 0.385 mmol) 1H). (xc) 6-(2-chloro-6-6-bromo-5-(3- Mass (400 MHz, DMSO) δ: methylpyridin-4-yl)-5-fluorophenyl)-1,2,4- spectroscopy: m/z 2.40 (s, 3H), 7.13-(3-fluorophenyl)- triazin-3-amine (90 (Cl) 316.6/318.6 7.16 (m, 1H),7.16- 1,2,4-triazin-3-amine mg, 0.334 mmol) and (M + H)⁺ (ES⁺); 7.21 (m,1H), 7.27- (54 mg, 0.171 mmol, 2-chloro-6-methyl-4- 314.8/316.8 (M − H)⁻7.29 (m, 1H), 7.29- 51.1%) (4,4,5,5-tetramethyl- (ES⁻), at 4.05 min,7.39 (m, 2H), 7.40- 1,3,2-dioxaborolan-2- 99.9% (method B). 7.48 (m,1H), 7.78 (s, yl)pyridine (98 mg, 2H). 0.385 mmol) (xci)4-(3-amino-5-(4- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ:fluorophenyl)-1,2,4- fluorophenyl)-1,2,4- spectroscopy: m/z 2.39 (s,6H), 7.19- triazin-6-yl)-2,6- triazin-3-amine (90 320.7 (M + H)⁺ 7.28(m, 4H), 7.46 dimethylbenzonitrile mg, 0.334 mmol) and (ES⁺); 318.9 (M −H)⁻ (dd, J 8.8, 5.5, 2H), (66 mg, 0.206 mmol, 2,6-dimethyl-4- (ES⁻), at4.40 min, 7.59 (s, 2H). 61.7%) (4,4,5,5-tetramethyl- 99.8% (method B).1,3,2-dioxaborolan-2- yl)benzonitrile (99 mg, 0.385 mmol) (xcii)6-(3-chloro-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:propoxyphenyl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 0.88 (t, J7.4, 3H), phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) (Cl) 341.6/343.61.52-1.64 (m, 2H), 3-amine (71 mg, and 2-(3-chloro-5- (M + H)⁺ (ES⁺);3.80 (t, J 6.6, 2H), 0.202 mmol, 56.3%) propoxyphenyl)- 339.8/341.8 (M −H)⁻ 6.75-6.80 (m, 1H), 4,4,5,5-tetramethyl- (ES⁻), at 5.14 min,6.94-6.99 (m, 2H), 1,3,2-dioxaborolane 96.9% (method B). 7.35-7.47 (m,5H), (106 mg, 0.358 7.50 (s, 2H). mmol) (xciii) 6-(3-chloro-5-6-bromo-5-(4- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe-fluorophenyl)-1,2,4- spectroscopy: m/z 7.25 (t, J 8.9, 2H), nyl)-5-(4-triazin-3-amine (90 (Cl) 369.4/371.5 7.47 (dd, J 8.8, 5.5,fluorophenyl)-1,2,4- mg, 0.334 mmol) and (M + H)⁺ (ES⁺); 2H), 7.57 (s,1H), triazin-3-amine (65 2-(3-chloro-5- 367.7/369.7 (M − H)⁻ 7.64 (s,2H), 7.74 (s, mg, 0.169 mmol, (trifluoromethyl)phe- (ES⁻), at 5.03 min,1H), 7.84 (s, 1H). 50.5%) nyl)-4,4,5,5- 95.8% (method B).tetramethyl-1,3,2- dioxaborolane (118 mg, 0.385 mmol) (xciv)6-(2-chloropyridin-4- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: yl)-5-(4-fluorophenyl)-1,2,4- spectroscopy: m/z 7.21-7.33 (m, 3H),fluorophenyl)-1,2,4- triazin-3-amine (90 (Cl) 302.7/304.7 7.44-7.53 (m,3H), triazin-3-amine (14 mg, 0.334 mmol) and (M + H)⁺ (ES⁺); 7.75 (s,2H), 8.35 (d, mg, 0.046 mmol, 2-chloro-4-(4,4,5,5- 300.9/302.9 (M − H)⁻J 5.1, 1H). 13.76%) tetramethyl-1,3,2- (ES⁻), at 3.90 min,dioxaborolan-2- 99.2% (method B). yl)pyridine (92 mg, 0.385 mmol) (xcv)6-(2-chloro-6- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ:methylpyridin-4-yl)-5- fluorophenyl)-1,2,4- spectroscopy: m/z 2.40 (s,3H), 7.15 (s, (4-fluorophenyl)- triazin-3-amine (90 (Cl) 316.7/318.71H), 7.23-7.31 (m, 1,2,4-triazin-3-amine mg, 0.334 mmol) and (M + H)⁺(ES⁺); 3H), 7.48 (dd, J 8.9, (37 mg, 0.117 mmol, 2-chloro-6-methyl-4-314.9/316.9 (M − H)⁻ 5.5, 2H), 7.72 (s, 2H). 34.9%)(4,4,5,5-tetramethyl- (ES⁻), at 4.05 min, 1,3,2-dioxaborolan-2- 99.5%(method B). yl)pyridine (98 mg, 0.385 mmol) (xcvi) 4-(3-amino-5-(4-6-bromo-5-(4- Mass (400 MHz, DMSO) δ: chlorophenyl)-1,2,4-chlorophenyl)-1,2,4- spectroscopy: m/z 2.40 (s, 6H), 7.25 (s,triazin-6-yl)-2,6- triazin-3-amine (90 (Cl) 336.6/338.6 2H), 7.40-7.50(m, dimethylbenzonitrile mg, 0.315 mmol) and (M + H)⁺ (ES⁺); 4H), 7.61(s, 2H). (61 mg, 0.181 mmol, 2,6-dimethyl-4- 334.8/336.8 (M − H)⁻ 57.4%)(4,4,5,5-tetramethyl- (ES⁻), at 4.67 min, 1,3,2-dioxaborolan-2- 99.6%(method B). yl)benzonitrile (81 mg, 0.315 mmol) (xcvii) 6-(3-chloro-5-6-bromo-5-(4- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe-chlorophenyl)-1,2,4- spectroscopy: m/z 7.40-7.51 (m, 4H), nyl)-5-(4-triazin-3-amine (90 (2 Cl) 385.3/387.4 7.59 (s, 1H), 7.67 (s,chlorophenyl)-1,2,4- mg, 0.315 mmol) and (M + H)⁺ (ES⁺); 2H), 7.74 (s,1H), triazin-3-amine (62.5 2-(3-chloro-5- 383.5/385.5 (M − H)⁻ 7.85 (s,1H). mg, 0.157 mmol, (trifluoromethyl)phe- (ES⁻), at 5.25 min, 49.7%)nyl)-4,4,5,5- 96.6% (method B). tetramethyl-1,3,2- dioxaborolane (111mg, 0.362 mmol) (xcviii) 5-(4-chlorophenyl)-6- 6-bromo-5-(4- Mass (400MHz, DMSO) δ: (2-chloropyridin-4-yl)- chlorophenyl)-1,2,4- spectroscopy:m/z 7.27 (dd, J 5.2, 1.5, 1,2,4-triazin-3-amine triazin-3-amine (90 (2Cl) 318.6/320.6 1H), 7.41-7.54 (m, (12.7 mg, 0.039 mg, 0.315 mmol) and(M + H)⁺ (ES⁺); 5H), 7.77 (s, 2H), mmol, 12.44%) 2-chloro-4-(4,4,5,5-316.8/318.8 (M − H)⁻ 8.35 (dd, J 5.2, 0.6, tetramethyl-1,3,2- (ES⁻), at4.22 min, 1H). dioxaborolan-2- 98.2% (method B). yl)pyridine (87 mg,0.362 mmol) (xcix) 6-(2-chloro-6- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ:methylpyridin-4-yl)-5- chlorophenyl)-1,2,4- spectroscopy: m/z 2.41 (s,3H), 7.14- (4-chlorophenyl)- triazin-3-amine (90 (2 Cl) 332.5/334.6 7.18(m, 1H), 7.27- 1,2,4-triazin-3-amine mg, 0.315 mmol) (M + H)⁺ (ES⁺);7.31 (m, 1H), 7.42- (46.1 mg, 0.138 and 2-chloro-6- 330.8/332.7 (M − H)⁻7.54 (m, 4H), 7.74 (s, mmol, 43.9%) methyl-4-(4,4,5,5- (ES⁻), at 4.37min, 2H). tetramethyl-1,3,2- 99.6% (method B). dioxaborolan-2-yl)pyridine (92 mg, 0.362 mmol) (c) 4-(3-amino-5-(3- 6-bromo-5-(3- Mass(400 MHz, DMSO) δ: chlorophenyl)-1,2,4- chlorophenyl)-1,2,4-spectroscopy: m/z 2.40 (s, 6H), 7.20 triazin-6-yl)-2,6- triazin-3-amine(90 (Cl) 336.6/338.6 (ddd, J 7.8, 1.6, 1.0, dimethylbenzonitrile mg,0.315 mmol) and (M + H)⁺ (ES⁺); 1H), 7.36 (app t, J (64.3 mg, 0.1902,6-dimethyl-4- 334.8/336.8 (M − H)⁻ 7.9, 1H), 7.26 (s, 2H), mmol,60.3%) (4,4,5,5-tetramethyl- (ES⁻), at 4.59 min, 7.53 (ddd, J 8.0, 2.2,1,3,2-dioxaborolan-2- 99.3% (method B). 1.0, 1H), 7.59 (app t,yl)benzonitrile (81 J 1.7, 1H), 7.64 (s, mg, 0.315 mmol) 2H). (ci)6-(3-chloro-5- 6-bromo-5-(3- Mass (400 MHz, DMSO) δ:(trifluoromethyl)phe- chlorophenyl)-1,2,4- spectroscopy: m/z 7.24-7.29(m, 1H), nyl)-5-(3- triazin-3-amine (90 (2 Cl) 385.3/387.4 7.39 (app td,J 7.8, chlorophenyl)-1,2,4- mg, 0.315 mmol) and (M + H)⁺ (ES⁺); 0.6,1H), 7.51-7.57 triazin-3-amine (67.6 2-(3-chloro-5- 383.5/385.6 (M − H)⁻(m, 2H), 7.57-7.61 mg, 0.169 mmol. (trifluoromethyl)phe- (ES⁻), at 5.20min, (m, 1H), 7.69 (s, 2H), 53.7%) nyl)-4,4,5,5- 96.4% (method B).7.75-7.79 (m, 1H), tetramethyl-1,3,2- 7.84-7.88 (m, 1H). dioxaborolane(111 mg, 0.362 mmol) (cii) 5-(3-chlorophenyl)-6- 6-bromo-5-(3- Mass (400MHz, DMSO) δ: (2-chloropyridin-4-yl)- chlorophenyl)-1,2,4- spectroscopy:m/z 7.25-7.29 (m, 1H), 1,2,4-triazin-3-amine triazin-3-amine (90 (2 Cl)318.6/320.6 7.31 (dd, J 5.2, 1.5, (32.4 mg, 0.101 mg, 0.315 mmol) (M +H)⁺ (ES⁺); 1H), 7.40 (app t, J mmol, 32.0%) and 2-chloro-4- 316.8/318.8(M − H)⁻ 11.9, 1H), 7.49-7.53 (4,4,5,5-tetramethyl- (ES⁻), at 4.17 min,(m, 1H), 7.54-7.61 1,3,2-dioxaborolan-2- 99.0% (method B). (m, 2H), 7.80(s, 2H), yl)pyridine (87 mg, 8.36 (dd, J 5.2, 0.6, 0.362 mmol) 1H).(ciii) 6-(2-chloro-6- 6-bromo-5-(3- Mass (400 MHz, DMSO) δ:methylpyridin-4-yl)-5- chlorophenyl)-1,2,4- spectroscopy: m/z 2.41 (s,3H), 7.19- (3-chlorophenyl)- triazin-3-amine (90 (2 Cl) 332.5/334.6 7.15(m, 1H), 7.26 1,2,4-triazin-3-amine mg, 0.315 mmol) and (M + H)⁺ (ES⁺);(ddd, J 7.8, 1.6, 1.1, (51.3 mg, 0.154 2-chloro-6-methyl-4- 330.8/332.7(M − H)⁻ 1H), 7.33-7.29 (m, mmol, 49.0%) (4,4,5,5-tetramethyl- (ES⁻), at4.30 min, 1H), 7.41 (app t, J 1,3,2-dioxaborolan-2- 100% (method B).7.9, 1H), 7.57 (ddd, J yl)pyridine (92 mg, 8.0, 2.2, 1.0, 1H), 0.362mmol) 7.60 (app t, J 1.7, 1H), 7.78 (s, 2H). (civ) 4-(3-amino-6-(3-4-(3-amino-6-bromo- Mass (400 MHz, DMSO) δ: chloro-5- 1,2,4-triazin-5-spectroscopy: m/z 7.54-7.58 (m, 1H), (trifluoromethyl)phe-yl)benzonitrile (90 (Cl) 376.4/378.4 7.57-7.62 (m, 2H),nyl)-1,2,4-triazin-5- mg, 0.326 mmol) and (M + H)⁺ (ES⁺); 7.65-7.81 (m,3H), yl)benzonitrile (64.7 2-(3-chloro-5- 374.6/376.6 (M − H)⁻ 7.83-7.87(m, 1H), mg, 0.171 mmol, (trifluoromethyl)phe- (ES⁻), at 4.67 min,7.87-7.93 (m, 2H). 52.5%) nyl)-4,4,5,5- 99.4% (method B).tetramethyl-1,3,2- dioxaborolane (115 mg, 0.375 mmol) (cv)4-(3-amino-6-(2- 4-(3-amino-6-bromo- Mass (400 MHz, DMSO) δ: chloro-6-1,2,4-triazin-5- spectroscopy: m/z 2.40 (s, 3H), 7.16 (s,methylpyridin-4-yl)- yl)benzonitrile (90 (Cl) 323.6/325.6 1H), 7.26 (s,1H), 1,2,4-triazin-5- mg, 0.326 mmol) (M + H)⁺ (ES⁺); 7.58-7.64 (m, 2H),yl)benzonitrile (30.5 and 2-chloro-6- 321.8/323.8 (M − H)⁻ 7.82 (s, 2H),7.88- mg, 0.093 mmol, methyl-4-(4,4,5,5- (ES⁻), at 3.65 min, 7.94 (m,2H). 28.6%) tetramethyl-1,3,2- 98.6% (method B). dioxaborolan-2-yl)pyridine (95 mg, 0.375 mmol) (cvi) 4-(3-amino-5-(3-6-bromo-5-(3-chloro- Mass (400 MHz, DMSO) δ: chloro-5- 5-fluorophenyl)-spectroscopy: m/z 2.41 (s, 6H), 7.11- fluorophenyl)-1,2,4-1,2,4-triazin-3-amine 354, 356 (M + H)⁺ 7.19 (m, 1H), 7.27 (s,triazin-6-yl)-2,6- (90 mg, 0.297 mmol) (ES⁺); 352, 354 (M − 2H),7.34-7.38 (m, dimethylbenzonitrile and 2,6-dimethyl-4- H)⁻ (ES⁻), at1H), 7.55-7.62 (m, (57 mg, 52%) (4,4,5,5-tetramethyl- 4.72 min, 95% 1H),7.70 (s, 2H). 1,3,2-dioxaborolan-2- (method B). yl)benzonitrile (88 mg,0.341 mmol) (cvii) 5-(3-chloro-5- 6-bromo-5-(3-chloro- Mass (400 MHz,DMSO) δ: fluorophenyl)-6-(2- 5-fluorophenyl)- spectroscopy: m/z 2.42 (s,3H), 7.19 (s, chloro-6- 1,2,4-triazin-3-amine 350, 352 (M + H)⁺ 1H),7.20-7.26 (m, methylpyridin-4-yl)- (90 mg, 0.297 mmol) (ES⁺); 348, 350(M − 1H), 7.30 (s, 1H), 1,2,4-triazin-3-amine and 2-chloro-6- H)⁻ (ES⁻),at 4.2 min, 7.38 (s, 1H), 7.58- (18 mg, 16%) methylpyridin-4- 95%(method B). 7.66 (m, 1H), 7.84 (s, ylboronic acid (58.4 2H). mg, 0.341mmol) (cviii) 6-(3-chloro-5- 6-bromo-5-(3-chloro- Mass (400 MHz, DMSO)δ: (trifluoromethyl)phe- 5-fluorophenyl)- spectroscopy: m/z 7.22 (ddd, J9.3, 2.4, nyl)-5-(3-chloro-5- 1,2,4-triazin-3-amine 403, 405 (M + H)⁺1.4, 1H), 7.34-7.39 fluorophenyl)-1,2,4- (90 mg, 0.297 mmol) (ES⁺); 401,403 (M − (m, 1H), 7.58-7.64 triazin-3-amine (28 and 2-(3-chloro-5- H)⁻(ES⁻), at (m, 2H), 7.76 (s, 2H), mg, 22%) (trifluoromethyl)phe- 5.28min, 93% 7.79 (s, 1H), 7.89 (s, nyl)-4,4,5,5- (method B). 1H).tetramethyl-1,3,2- dioxaborolane (105 mg, 0.341 mmol) (cix)6-(3-chloro-5- 6-bromo-5-(3,5- Mass (400 MHz, DMSO) δ:(trifluoromethyl)phe- difluorophenyl)-1,2,4- spectroscopy: m/z 7.08-7.20(m, 2H), nyl)-5-(3,5- triazin-3-amine (90 387, 389 (M + H)⁺ 7.42 (tt, J9.3, 2.4, difluorophenyl)-1,2,4- mg, 0.314 mmol) and (ES⁺); 385, 387 (M− 1H), 7.58 (s, 1H), triazin-3-amine (54 2-(3-chloro-5- H)⁻ (ES⁻), at7.66-7.86 (m, 3H), mg, 43%) (trifluoromethyl)phe- 5.09 min, 96% 7.89 (s,1H). nyl)-4,4,5,5- (method B). tetramethyl-1,3,2- dioxaborolane (96 mg,0.314 mmol) (cx) 6-(2-chloro-6- 6-bromo-5-(3,5- Mass (400 MHz, DMSO) δ:methylpyridin-4-yl)-5- difluorophenyl)-1,2,4- spectroscopy: m/z 2.42 (s,3H), 7.11- (3,5-difluorophenyl)- triazin-3-amine (90 334, 336 (M + H)⁺7.18 (m, 2H), 7.17- 1,2,4-triazin-3-amine mg, 0.314 mmol) and (ES⁺);332, 334 (M − 7.20 (m, 1H), 7.25- (29 mg, 27%) 2-chloro-6- H)⁻ (ES⁻), at7.31 (m, 1H), 7.44 (tt, methylpyridin-4- 4.17 min, 98% J 9.3, 2.4, 1H),7.82 ylboronic acid (61.8 (method B). (s, 2H). mg, 0.361 mmol) (cxi)4-(3-amino-5-(3,5- 6-bromo-5-(3,5- Mass (400 MHz, DMSO) δ:difluorophenyl)-1,2,4- difluorophenyl)-1,2,4- spectroscopy: m/z 2.41 (s,6H), 7.05- triazin-6-yl)-2,6- triazin-3-amine (90 338 (M + H)⁺ (ES⁺);7.14 (m, 2H), 7.26 (s, dimethylbenzonitrile mg, 0.314 mmol) and 336 (M −H)⁻ (ES⁻), at 2H), 7.40 (tt, J 9.3, (48 mg, 45%) 2,6-dimethyl-4- 4.45min, 100% 2.4, 1H), 7.69 (s, 2H). (4,4,5,5-tetramethyl- (method B).1,3,2-dioxaborolan-2- yl)benzonitrile (93 mg, 0.361 mmol) (cxii)4-(3-amino-5-(3- 6-bromo-5-(3-chloro- Mass (400 MHz, DMSO) δ: chloro-4-4-fluorophenyl)- spectroscopy: m/z 2.41 (s, 6H), 7.22-fluorophenyl)-1,2,4- 1,2,4-triazin-3-amine 354, 356 (M + H)⁺ 7.28 (m,1H), 7.28 (s, triazin-6-yl)-2,6- (90 mg, 0.297 mmol) (ES⁺); 352, 354 (M− 2H), 7.37-7.44 (m, dimethylbenzonitrile and 2,6-dimethyl-4- H)⁻ (ES⁻),at 1H), 7.66 (s, 2H), (35 mg, 33%) (4,4,5,5-tetramethyl- 4.67 min, 98%7.75 (dd, J 7.2, 2.2, 1,3,2-dioxaborolan-2- (method B). 1H).yl)benzonitrile (88 mg, 0.341 mmol) (cxiii) 5-(3-chloro-4-6-bromo-5-(3-chloro- Mass (400 MHz, DMSO) δ: fluorophenyl)-6-(2-4-fluorophenyl)- spectroscopy: m/z 2.42 (s, 3H), 7.21 (s, chloro-6-1,2,4-triazin-3-amine 350, 352 (M + H)⁺ 1H), 7.30 (s, 1H),methylpyridin-4-yl)- (90 mg, 0.297 mmol) (ES⁺); 348, 350 (M − 7.30-7.35(m, 1H), 1,2,4-triazin-3-amine and 2-chloro-6- H)⁻ (ES⁻), at 7.46 (appt, J 8.9, (40 mg, 38%) methylpyridin-4- 4.39 min, 99% 1H), 7.66-7.91 (m,ylboronic acid (61.8 (method B). 3H). mg, 0.361 mmol) (cxiv)5-(3-chloro-4- 6-bromo-5-(3,5- Mass (400 MHz, DMSO) δ:fluorophenyl)-6-(2- difluorophenyl)-1,2,4- spectroscopy: m/z 7.30 (dd, J5.2, 1.5, chloropyridin-4-yl)- triazin-3-amine (90 336, 338 (M + H)⁺1H), 7.34 (ddd, J 8.6, 1,2,4-triazin-3-amine mg, 0.314 mmol) and (ES⁺);334, 336 (M − 4.7, 2.2, 1H), 7.42- (9 mg, 9%) 2-chloropyridin-4- H)⁻(ES⁻), at 4.2 min, 7.51 (m, 1H), 7.53- ylboronic acid (61.8 98% (methodB). 7.57 (m, 1H), 7.75 mg, 0.361 mmol) (dd, J 7.2, 2.1, 1H), 7.82 (s,2H), 8.37 (dd, J 5.2, 0.6, 1H). (cxv) 5-(3-chloro-4-6-bromo-5-(3-chloro- Mass (400 MHz, DMSO) δ: fluorophenyl)-6-(3-4-fluorophenyl)- spectroscopy: m/z 7.33 (ddd, J 8.6, 4.7, chloro-5-1,2,4-triazin-3-amine 403, 405 (M + H)⁺ 2.2, 1H), 7.45 (app t,(trifluoromethyl)phe- (90 mg, 0.297 mmol) (ES⁺); 401, 403 (M − J 8.9,1H), 7.61 (s, nyl)-1,2,4-triazin-3- and 2-(3-chloro-5- H)⁻ (ES⁻), at1H), 7.63-7.76 (m, amine (50 mg, 42%) (trifluoromethyl)phe- 5.22 min,100% 3H), 7.78 (s, 1H), nyl)-4,4,5,5- (method B). 7.88 (s, 1H).tetramethyl-1,3,2- dioxaborolane (91 mg, 0.297 mmol) (cxvi)4-(3-amino-5-(3,4- 6-bromo-5-(3,4- Mass (400 MHz, DMSO) δ:difluorophenyl)-1,2,4- difluorophenyl)-1,2,4- spectroscopy: m/z 2.41 (s,6H), 7.10- triazin-6-yl)-2,6- triazin-3-amine (90 338 (M + H)⁺ (ES⁺);7.20 (m, 1H), 7.26 (s, dimethylbenzonitrile mg, 0.314 mmol) and 336 (M −H)⁻ (ES⁻), at 2H), 7.40-7.50 (m, (35 mg, 33%) 2,6-dimethyl-4- 4.49 min,99% 1H), 7.54 (ddd, J (4,4,5,5-tetramethyl- (method B). 11.4, 7.8, 2.1,1H), 1,3,2-dioxaborolan-2- 7.65 (s, 2H). yl)benzonitrile (93 mg, 0.361mmol) (cxvii) 6-(2-chloro-6- 6-bromo-5-(3,4- Mass (400 MHz, DMSO) δ:methylpyridin-4-yl)-5- difluorophenyl)-1,2,4- spectroscopy: m/z 2.41 (s,3H), 7.20 (s, (3,4-difluorophenyl)- triazin-3-amine (90 334, 336 (M +H)⁺ 1H), 7.20-7.24 (m, 1,2,4-triazin-3-amine mg, 0.314 mmol) and (ES⁺);332, 334 (M − 1H), 7.28 (s, 1H), (28 mg, 27%) 2-chloro-6- H)⁻ (ES⁻), at7.44-7.62 (m, 2H), methylpyridin-4- 4.15 min, 99% 7.79 (s, 2H).ylboronic acid (61.8 (method B). mg, 0.361 mmol) (cxviii)6-(2-chloropyridin-4- 6-bromo-5-(3,4- Mass (400 MHz, DMSO) δ:yl)-5-(3,4- difluorophenyl)-1,2,4- spectroscopy: m/z 7.18-7.26 (m, 1H),difluorophenyl)-1,2,4- triazin-3-amine (90 320, 322 (M + H)⁺ 7.28 (dd, J5.2, 1.5, triazin-3-amine (10 mg, 0.314 mmol) and (ES⁺); 318, 320 (M −1H), 7.44-7.62 (m, mg, 10%) 2-chloropyridin-4- H)⁻ (ES⁻), at 4.0 min,3H), 7.81 (s, 2H), ylboronic acid (56.7 96% (method B). 8.36 (dd, J 5.2,0.6, mg, 0.361 mmol) 1H). (cxix) 6-(3-chloro-5- 6-bromo-5-(3,4- Mass(400 MHz, DMSO) δ: (trifluoromethyl)phe- difluorophenyl)-1,2,4-spectroscopy: m/z 7.17-7.26 (m, 1H), nyl)-5-(3,4- triazin-3-amine (90387, 389 (M + H)⁺ 7.43-7.57 (m, 2H), difluorophenyl)-1,2,4- mg, 0.314mmol) and (ES⁺); 385, 387 (M − 7.59 (s, 1H), 7.71 (s, triazin-3-amine(16 2-(3-chloro-5- H)⁻ (ES⁻), at 2H), 7.76 (s, 1H), mg, 13%)(trifluoromethyl)phe- 5.07 min, 95% 7.87 (s, 1H). nyl)-4,4,5,5- (methodB). tetramethyl-1,3,2- dioxaborolane (96 mg, 0.314 mmol) (cxx)6-(3-chloro-5- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ:(trifluoromethyl)phe- (methoxymethyl)phe- spectroseopy: m/z 3.26 (s,3H), 4.43 (s, nyl)-5-(4- nyl)-1,2,4-triazin-3- (Cl) 395.3/397.3 2H),7.33 (d, J 8.5, (methoxymethyl)phe- amine (90 mg, 0.305 (M + H)⁺ (ES⁺);2H), 7.39 (d, J 8.4, nyl)-1,2,4-triazin-3- mmol) and 2-(3- 393.5/395.5(M − H)⁻ 2H), 7.57 (s, 1H), amine (36 mg, 0.087 chloro-5- (ES⁻), at 4.93min, 7.64 (s, 2H), 7.72 (s, mmol, 28.7%) (trifluoromethyl)phe- 95.9%(method B). 1H), 7.83 (s, 1H). nyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (107 mg, 0.351 mmol) (cxxi) 6-(2-chloro-6- 6-bromo-5-(4-Mass (400 MHz, DMSO) δ: methylpyridin-4-yl)-5- (methoxymethyl)phe-spectroscopy: m/z 2.39 (s, 3H), 3.28 (s, (4- nyl)-1,2,4-triazin-3- (Cl)342.6/344.5 3H), 4.45 (s, 2H), (methoxymethyl)phe- amine (90 mg, 0.305(M + H)⁺ (ES⁺); 7.08-7.14 (m, 1H), nyl)-1,2,4-triazin-3- mmol) and2-chloro- 340.8/342.8 (M − H)⁻ 7.25-7.31 (m, 1H), amine (23 mg, 0.0666-methyl-4-(4,4,5,5- (ES⁻), at 3.93 min, 7.35 (d, J 8.5, 2H), mmol,21.49%) tetramethyl-1,3,2- 97.4% (method B). 7.41 (d, J 8.4, 2H),dioxaborolan-2- 7.72 (s, 2H). yl)pyridine (89 mg, 0.351 mmol) (cxxii)6-(2,6- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: dimethylpyridin-4-yl)-fluorophenyl)-1,2,4- spectroscopy: m/z 2.40 (s, 6H), 7.10 (s,5-(4-fluorophenyl)- triazin-3-amine (90 296.8 (M + H)⁺ 2H), 7.20-7.31(m, 1,2,4-triazin-3-amine mg, 0.334 mmol) and (ES⁺); 295.0 (M − H)⁻ 2H),7.40-7.53 (m, (23 mg, 0.078 mmol, 2,6-dimethylpyridin- (ES⁻), at 3.85min, 2H), 7.68 (s, 2H). 23.19%) 4-ylboronic acid 99.6% (method B). (58.1mg, 0.385 mmol) (cxxiii) 6-(3-chloro-5- 6-bromo-5-(4- Mass (400 MHz,DMSO) δ: methylphenyl)-5-(4- fluorophenyl)-1,2,4- spectroscopy: m/z 2.25(s, 3H), 7.10- fluorophenyl)-1,2,4- triazin-3-amine (90 (Cl) 315.6/317.67.17 (m, 2H), 7.19- triazin-3-amine (67 mg, 0.334 mmol) and (M + H)⁺(ES⁺); 7.28 (m, 3H), 7.42- mg, 0.212 mmol, 3-chloro-5- 313.8/315.8 (M −H)⁻ 7.49 (m, 2H), 7.51 (s, 63.3%) methylphenylboronic (ES⁻), at 4.82min, 2H). acid (65.5 mg, 0.385 99.4% (method B). mmol) (cxxiv)6-(6-fluoropyridin-3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:yl)-5-phenyl-1,2,4- 1,2,4-triazin-3-amine spectroscopy: 7.17 (ddd, J8.5, 2.8, triazin-3-amine (47 (75 mg, 0.299 mmol) m/z 268.2 (M + H)⁺0.5, 1H), 7.53 (s, 2H), mg, 0.173 mmol, and 2-fluoro-5- (ES⁺); 266.3 (M− H)⁻ 7.35-7.48 (m, 5H), 58.0%) (4,4,5,5-tetramethyl- (ES⁻), at 3.54min, 7.86-7.94 (m, 1H), 1,3,2-dioxaborolan-2- 98.5% (method B).8.13-8.19 (m, 1H). yl)pyridine (77 mg, 0.344 mmol) (cxxv) 6-(3,5-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: dimethylisoxazol-4-1,2,4-triazin-3-amine spectroscopy: 1.85 (s, 3H), 2.02 (s,yl)-5-phenyl-1,2,4- (75 mg, 0.299 mmol) m/z 268.2 (M + H)⁺ 3H),7.38-7.55 (m, triazin-3-amine (8 and 5- (ES⁺); 266.4 (M − H)⁻ 7H). mg,0.030 mmol, dimethylisoxazol-4- (ES⁻), at 3.48 min, 10.02%) ylboronicacid (42.1 96.2% (method B). mg, 0.299 mmol) (cxxvi) 6-(3,5-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: diisopropylphenyl)-5-1,2,4-triazin-3-amine spectroscopy: 1.06 (d, J 6.9, 12H),phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) m/z 333.3 (M + H)⁺ 2.78 (hept,J 6.8, 2H), 3-amine (84.5 mg, and 2-(3,5- (ES⁺); 331.5 (M − H)⁻6.96-7.06 (m, 3H), 0.254 mmol, 70.9%) diisopropylphenyl)- (ES⁻), at 5.24min, 7.31-7.45 (m, 7H). 4,4,5,5-tetramethyl- 100% (254 nm).1,3,2-dioxaborolane (119 mg, 0.412 mmol) (cxxvii) 6-(3-fluoro-5-(2,2,2-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: trifluoroethoxy)phenyl)-1,2,4-triazin-3-amine spectroscopy: 4.73 (q, J 8.8, 2H), 5-phenyl-1,2,4-(90 mg, 0.358 mmol) m/z 365.2 (M + H)⁺ 6.76 (ddd, J 9.5, 2.3,triazin-3-amine (80 and 3-fluoro-5-(2,2,2- (ES⁺); 363.4 (M − H)⁻ 1.4,1H), 6.89-6.94 mg, 0.214 mmol, trifluoroethoxy)phenyl- (ES⁻), at 4.43min, (m, 1H), 6.99 (dt, J 59.7%) boronic acid (98 mg, 97.4% (method B).10.7, 2.3, 1H), 7.52 0.412 mmol) (s, 2H), 7.34-7.48 (m, 5H). (cxxviii)N-(4-(3-amino-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:phenyl-1,2,4-triazin- 1,2,4-triazin-3-amine spectroscopy: 2.04 (s, 3H),7.34- 6-yl)-2- (90 mg, 0.358 mmol) m/z 374.1 (M + H)⁺ 7.48 (m, 5H),7.49- (trifluoromethyl)phe- and N-(4-(4,4,5,5- (ES⁺); 372.3 (M − H)⁻7.68 (m, 5H), 9.55 (s, nyl)acetamide (99 mg, tetramethyl-1,3,2- (ES⁻),at 3.52 min, 1H). 0.255 mmol, 71.0%) dioxaborolan-2-yl)-2- 98.9% (methodB). (trifluoromethyl)phe- nyl)acetamide (136 mg, 0.412 mmol) (cxxix)5-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:1,2,4-triazin-6-yl)-2- 1,2,4-triazin-3-amine spectroscopy: 7.34-7.42 (m,4H), fluorobenzonitrile (43 (90 mg, 0.358 mmol) m/z 292.1 (M + H)⁺7.42-7.47 (m, 1H), mg, 0.147 mmol, and 3-cyano-4- (ES⁺); 290.3 (M − H)⁻7.50 (t, J 9.2, 1H), 40.9%) fluorophenylboronic (ES⁻), at 3.79 min, 7.57(s, 2H), 7.67 acid (68.0 mg, 0.412 99.3% (method B). (ddd, J 8.8, 5.3,2.3, mmol) 1H), 7.89 (dd, J 6.2, 2.3, 1H). (cxxx) 3-(3-amino-5-phenyl-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)-1,2,4-triazin-3-amine spectroscopy: 2.60 (s, 3H), 2.89 (s, N,N- (90 mg,0.358 mmol) m/z 320.2 (M + H)⁺ 3H), 7.19-7.24 (m, dimethylbenzamide and3- (ES⁺); 318.4 (M − H)⁻ 1H), 7.31-7.38 (m, (80 mg, 0.251 mmol,(dimethylcarbamoyl) (ES⁻), at 3.30 min, 3H), 7.38-7.47 (m, 69.9%)phenylboronic acid 100% (method B). 6H), 7.48-7.52 (m, (80 mg, 0.412mmol) 1H). (cxxxi) 6-(1-methyl-1H- 6-bromo-5-phenyl- Mass (400 MHz,DMSO) δ: pyrazol-4-yl)-5- 1,2,4-triazin-3-amine spectroscopy: 3.77 (s,3H), 7.04 (d, phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) m/z 253.2 (M+H)⁺J 0.7, 1H), 7.24 (s, 3-amine (43 mg, and 1-methyl-4- (ES⁺); 251.4 (M −H)⁻ 2H), 7.43-7.56 (m, 0.168 mmol, 47.0%) (4,4,5,5-tetramethyl- (ES⁻),at 3.15 min, 5H), 7.64 (s, 1H). 1,3,2-dioxaborolan-2- 98.8% (method B).yl)-1H-pyrazole (86 mg, 0.412 mmol) (cxxxii) 4-(3-amino-5-phenyl-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)-1-1,2,4-triazin-3-amine spectroscopy: 3.39 (s, 3H), 6.14methylpyridin-2(1H)- (90 mg, 0.358 mmol) m/z 280.1 (M + H)⁺ (dd, J 7.0,2.0, 1H), one (33 mg, 0.115 and 1-methyl-4- (ES⁺); 278.4 (M − H)⁻ 6.32(d, J 1.7, 1H), mmol, 32.1%) (4,4,5,5-tetramethyl- (ES⁻), at 2.92 min,7.38-7.54 (m, 5H), 1,3,2-dioxaborolan-2- 97.4% (method B). 7.56-7.70 (m,3H). yl)pyridin-2(1H)-one (97 mg, 0.412 mmol) (cxxxiii) 6-(3-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: morpholinophenyl)-5-1,2,4-triazin-3-amine spectroscopy: 2.87-3.02 (m, 4H),phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) m/z 334.3 (M + H)⁺ 3.58-3.72(m, 4H), 3-amine (65 mg, and 4-(3-(4,4,5,5- (ES⁺); 332.4 (M − H)⁻ 6.74(d, J 7.7, 1H), 0.192 mmol, 53.6%) tetramethyl-1,3,2- (ES⁻), at 4.07min, 6.86-6.94 (m, 2H), dioxaborolan-2- 98.6% (method B). 7.16 (t, J7.6, 1H), yl)phenyl)morpholine 7.28-7.45 (m, 7H). (119 mg, 0.412 mmol)(cxxxiv) 6-(1-benzyl-1H- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:pyrazol-4-yl)-5- 1,2,4-triazin-3-amine spectroscopy: 5.26 (s, 2H), 7.12-phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) m/z 329.3 (M + H)⁺ 7.18 (m,2H), 7.20 (d, 3-amine (78 mg, and 1-benzyl-4- (ES⁺); 327.5 (M − H)⁻ J0.7, 1H), 7.26 (s, 0.237 mmol, 66.1%) (4,4,5,5-tetramethyl- (ES⁻), at4.07 min, 2H), 7.27-7.37 (m, 1,3,2-dioxaborolan-2- 99.8% (method B).3H), 7.40-7.53 (m, yl)-1H-pyrazole (117 5H), 7.67 (d, J 0.7, mg, 0.412mmol) 1H). (cxxxv) 6-(2- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:methoxypyrimidin-5- 1,2,4-triazin-3-amine spectroscopy: 3.91 (s, 3H),7.38- yl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) m/z 281.2 (M + H)⁺ 7.49(m, 5H), 7.55 (s, triazin-3-amine (34 and 2- (ES⁺); 279.4 (M − H)⁻ 2H),8.50 (s, 2H). mg, 0.119 mmol, methoxypyrimidin-5- (ES⁻), at 3.42 min,33.2%) ylboronic acid (63.5 98.2% (method B). mg, 0.412 mmol) (cxxxvi)6-(6-methoxypyridin- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:3-yl)-5-phenyl-1,2,4- 1,2,4-triazin-3-amine spectroscopy: 3.84 (s, 3H),6.78 triazin-3-amine (50 (90 mg, 0.358 mmol) m/z 280.1 (M + H)⁺ (dd, J8.6, 0.7, 1H), mg, 0.176 mmol, and 6- (ES⁺); 278.4 (M − H)⁻ 7.34-7.48(m, 7H), 49.1%) methoxypyridin-3- (ES⁻), at 3.88 min, 7.60 (dd, J 8.6,2.5, ylboronic acid (63.0 98.3% (method B). 1H), 8.10 (dd, J 2.5, mg,0.412 mmol) 0.7, 1H). (cxxxvii) 6-(3- 6-bromo-5-phenyl- Mass (400 MHz,DMSO) δ: (methylsulfinyl)phe- 1,2,4-triazin-3-amine spectroscopy: 2.58(s, 3H), 7.32- nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) m/z 311.1 (M +H)⁺ 7.47 (m, 5H), 7.47- triazin-3-amine (70 and with 3- (ES⁺); 309.3 (M− H)⁻ 7.57 (m, 4H), 7.58- mg, 0.217 mmol, (methylsulfinyl)phenyl- (ES⁻),at 3.29 min, 7.60 (m, J 1.3, 1H), 60.4%) boronic acid (76 mg, 96.0%(method B). 7.63 (dt, J 7.3, 1.7, 0.412 mmol) 1H). (cxxxviii)4-(3-amino-6-(2- 4-(3-amino-6-bromo- Mass (400 MHz, DMSO) δ:chloropyridin-4-yl)- 1,2,4-triazin-5- spectroscopy: 7.25 (dd, J 5.2,1.5, 1,2,4-triazin-5- yl)benzonitrile (90 m/z (Cl) 1H), 7.51 (dd, J 1.5,yl)benzonitrile (11.3 mg, 0.326 mmol) and 309.6/311.7 (M + H)⁺ 0.7, 1H),7.58-7.65 mg, 0.036 mmol, 2-chloro-4-(4,4,5,5- (ES⁺); 307.9/309.9 (m,2H), 7.85 (s, 2H), 10.93%) tetramethyl-1,3,2- (M − H)⁻ (ES⁻), at7.89-7.94 (m, 2H), dioxaborolan-2- 3.50 min, 97.3% 8.34 (dd, J 5.2, 0.6,yl)pyridine (90 mg, (method B). 1H). 0.375 mmol) (cxxxix)4-(3-amino-5-(4- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ:(methoxymethyl)phe- (methoxymethyl)phe- spectroscopy: 2.38 (s, 6H), 4.43(s, nyl)-1,2,4-triazin-6- nyl)-1,2,4-triazin-3- m/z 346.6 (M + H)⁺ 2H),7.23 (s, 2H), yl)-2,6- amine (90 mg, 0.305 (ES⁺); 344.8 (M − H)⁻ 7.32(d, J 8.5, 2H), dimethylbenzonitrile mmol) and 2,6- (ES⁻), at 4.25 min,7.39 (d, J 8.4, 2H), (47 mg, 0.132 mmol, dimethyl-4-(4,4,5,5- 96.7%(method B). 7.67 (s, 2H). 43.2%) tetramethyl-1,3,2- dioxaborolan-2-yl)benzonitrile (78 mg, 0.305 mmol) (cxl) 6-(2-chloropyridin-4-6-bromo-5-(4- Mass (400 MHz, DMSO) δ: yl)-5-(4- (methoxymethyl)phe-spectroscopy: 3.29 (s, 3H), 4.45 (s, (methoxymethyl)phe-nyl)-1,2,4-triazin-3- m/z (Cl) 2H), 7.28 (dd, J 5.2,nyl)-1,2,4-triazin-3- amine (90 mg, 0.305 328.6/330.5 (M + H)⁺ 1.5, 1H),7.35 (d, J amine (26 mg, 0.077 mmol) and 2-chloro- (ES⁺); 326.8/328.88.5, 2H), 7.42 (d, J mmol, 25.3%) 4-(4,4,5,5- (M − H)⁻ (ES⁻), at 8.4,2H), 7.48 (dd, J tetramethyl-1,3,2- 3.79 min, 97.4% 1.5, 0.7, 1H), 7.74(s, dioxaborolan-2- (method B). 2H), 8.33 (dd, J 5.2, yl)pyridine (84mg, 0.7, 1H). 0.351 mmol) (cxli) 6(E)-5-phenyl-6- 6-bromo-5-phenyl- Mass(400 MHz, DMSO) δ: styryl-1,2,4-triazin-3- 1,2,4-triazin-3-aminespectroscopy: 7.09 (d, J 16.0, 1H), amine (27 mg, 0.098 (90 mg, 0.358mmol) m/z z 275.1 (M + H)⁺ 7.28 (t, J 7.3, 1H), mmol, 27.5%) and(E)-styrylboronic (ES⁺), at 4.78 min, 7.36 (t, J 7.5, 2H), acid (61.0mg, 0.412 93.2% (method B). 7.44 (s, 2H), 7.49 (d, mmol) J 7.3, 2H),7.55- 7.62 (m, 4H), 7.64- 7.70 (m, 2H). (cxlii) 6-(3-amino-5-phenyl-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-1,2,4-triazin-3-amine spectroscopy: 3.48 (s, 2H), 6.80 yl)indolin-2-one(34 (90 mg, 0.358 mmol) m/z 304.7 (M + H)⁺ (dd, J 7.6, 1.6, 1H), mg,0.111 mmol, and 2-oxoindolin-6- (ES⁺); 302.9 (M − H)⁻ 6.86-6.90 (m, 1H),31.0%) ylboronic acid (72.9 (ES⁻), at 3.47 min, 7.11 (d, J 7.7, 1H), mg,0.412 mmol) 99.1% (method B). 7.31-7.47 (m, 7H), 10.38 (s, 1H). (cxliii)tert-butyl 5-(3-amino- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:5-phenyl-1,2,4- 1,2,4-triazin-3-amine spectroscopy: 1.45 (s, 9H), 3.28(s, triazin-6-yl)pyridin-2- (90 mg, 0.358 mmol) m/z 379.5 (M + H)⁺ 3H),7.35-7.48 (m, yl(methyl)carbamate and 6-(tert- (ES⁺); 377.8 (M − H)⁻5H), 7.49 (s, 2H), (120 mg, 0.308 butoxycarbonyl(meth- (ES⁻), at 4.53min, 7.60 (dd, J 8.7, 0.8, mmol, 42.9%) yl)amino)pyridin-3- 97.1%(method B). 1H), 7.66 (dd, J 8.7, ylboronic acid (181 2.4, 1H), 8.30(dd, J mg, 0.717 mmol) 2.4, 0.8, 1H). (cxliv) 5-(3-chloro-5-6-bromo-5-(3-chloro- Mass (400 MHz, DMSO) δ: fluorophenyl)-6-(2-5-fluorophenyl)- spectroscopy: m/z 7.24 (ddd, J 9.2, 2.4,chloropyridin-4-yl)- 1,2,4-triazin-3-amine 336, 338 (M + H)⁺ 1.4 Hz,1H), 7.30 (dd, 1,2,4-triazin-3-amine (90 mg, 0.297 mmol), (ES⁺); 334,336 (M − J 5.2, 1.4 Hz, 1H), (22 mg, 22%) 2-chloropyridin-4- H)⁻ (ES⁻),at 7.39 (t, J 1.4 Hz, 1H), ylboronic acid (53.7 4.27 min, 100% 7.53 (dd,J 1.4, 0.6 mg, 0.341 mmol) purity (method B). Hz, 1H), 7.59-7.65 (m,1H), 7.85 (s, 2H), 8.38 (dd, J 5.2, 0.6 Hz, 1H). (cxlv)6-(2-chloropyridin-4- 6-bromo-5-(3,5- Mass ((400 MHz, DMSO) δ:yl)-5-(3,5- difluorophenyl)-1,2,4- spectroscopy: m/z 7.11-7.24 (m, 2H),difluorophenyl)-1,2,4- triazin-3-amine (90 320, 322 (M + H)⁺ 7.30 (dd, J5.1, 1.4 triazin-3-amine (22 mg, 0.314 mmol), 2- (ES⁺); 318, 320 (M −Hz, 1H), 7.43 (tt, J mg, 22%) chloropyridin-4- H)⁻ (ES⁻), at 9.3, 2.4Hz, 1H), 7.53 ylboronic acid (56.7 3.98 min, 98% purity (dd, J 1.4, 0.6Hz, mg, 0.361 mmol) (method B) 1H), 7.84 (s, 2H), 8.38 (dd, J 5.1, 0.6Hz, (cxlvi) 4-(3-amino-5-(4- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ:(difluoromethoxy)phe- (difluoromethoxy)phe- spectroscopy: m/z 2.39 (s,6H), 7.15- nyl)-1,2,4-triazin-6- nyl)-1,2,4-triazin-3- 368 (M + H)⁺(ES⁺); 7.21 (m, 2H), 7.24 (s, yl)-2,6- amine (90 mg, 0.284 366 (M − H)⁻(ES⁻), at 2H), 7.31 (t, ²J_(HF) 72 dimethylbenzonitrile mmol),2,6-dimethyl- 4.42 min, 99% purity Hz, 1H), 7.43-7.48 (32 mg, 30%)4-(4,4,5,5- (method B). (m, 2H), 7.57 (s, 2H). tetramethyl-1,3,2-dioxaborolan-2- yl)benzonitrile (84 mg, 0.326 mmol) (cxlvii)6-(2-chloro-6- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ:methylpyridin-4-yl)-5- (difluoromethoxy)phe- spectroscopy: m/z 2.40 (s,3H), 7.17 (s, (4- nyl)-1,2,4-triazin-3- 364, 366 (M + H)⁺ 1H), 7.22 (d,J 8.7 (difluoromethoxy)phe- amine (90 mg, 0.284 (ES⁺); 362, 364 (M − Hz,2H), 7.27 (d, J nyl)-1,2,4-triazin-3- mmol), 2-chloro-6- H)⁻ (ES⁻), at0.7 Hz, 1H), 7.33 (t, amine (15 mg, 14%) methylpyridin-4- 4.14 min, 98%purity ²J_(HF) 72 Hz, 1H), 7.46- ylboronic acid (55.9 (method B). 7.51(m, 2H), 7.71 mg, 0.326 mmol) (s, 2H). (cxlviii) 6-(2-chloropyridin-4-6-bromo-5-(4- Mass (400 MHz, DMSO) δ: yl)-5-(4- (difluoromethoxy)phe-spectroscopy: m/z 7.21 (d, J 8.7 Hz, (difluoromethoxy)phe-nyl)-1,2,4-triazin-3- 350, 352 (M + H)⁺ 2H), 7.29 (dd, J 5.2,nyl)-1,2,4-triazin-3- amine (90 mg, 0.284 (ES⁺); 348, 350 (M − 1.5 Hz,1H), 7.34 (t, amine (17 mg, 17%) mmol), 2- H)⁻ (ES⁻), at 4.0 ²J_(HF) 72Hz, 1H), 7.46- chloropyridin-4- min, 98% purity 7.55 (m, 3H), 7.73ylboronic acid (51.4 (method B) (s, 2H), 8.35 (dd, J mg, 0.326 mmol)5.2, 0.6 Hz, 1H). (cxlix) 6-(3-chloro-5- 6-bromo-5-(4- Mass (400 MHz,DMSO) δ: (trifluoromethyl)phe- (difluoromethoxy)phe- spectroscopy: m/z7.17-7.23 (m, 2H), nyl)-5-(4- nyl)-1,2,4-triazin-3- 417, 419 (M + H)⁺7.31 (t, ²J_(HF) 72 Hz, (difluoromethoxy)phe- amine (90 mg, 0.284 (ES⁺);415, 417 (M − 1H), 7.44-7.50 (m, nyl)-1,2,4-triazin-3- mmol),2-(3-chloro-5- H)⁻ (ES⁻), at 5.02 2H), 7.56-7.59 (m, amine (67 mg, 54%)(trifluoromethyl)phe- min, 95% purity 1H), 7.63 (s, 2H), nyl)-4,4,5,5-(method B). 7.74-7.75 (m, 1H), tetramethyl-1,3,2- 7.84-7.85 (m, 1H).dioxaborolane (87 mg, 0.284 mmol) (cl) 5-(3-amino-5-(3- 6-bromo-5-(3-Mass (400 MHz, DMSO) δ: fluorophenyl)-1,2,4- fluorophenyl)-1,2,4-spectroscopy: m/z 6.64 (dd, J 8.2, 2.0 triazin-6-yl)-2- triazin-3-amine(90 317, 319 (M + H)⁺ Hz, 1H), 7.07 (d, J chlorophenol (16 mg, mg, 0.334mmol), 4- (ES⁺); 315, 317 (M − 2.0 Hz, 1H), 7.23 (d, 15%) chloro-3- H)⁻(ES⁻), at J 8.2 Hz, 1H), 7.34- hydroxyphenylboronic 2.68 min, 97% purity7.48 (m, 7H), 10.26 acid (57.7 mg, (method B). (s, 1H). 0.334 mmol)(cli) 4-(3-amino-6-(3- 4-(3-amino-6-bromo- Mass (400 MHz, DMSO) δ:chloro-4- 1,2,4-triazin-5- spectroscopy: m/z 6.80-6.93 (m, 1H),hydroxyphenyl)- yl)benzonitrile (75 (Cl) 324.2/326.3 6.99 (dd, J 8.4,2.2 1,2,4-triazin-5- mg, 0.272 mmol) and (M + H)⁺ (ES+); Hz, 1H), 7.36(d, J yl)benzonitrile (21 2-chloro-4-(4,4,5,5- 322.1/324.2 (M − H)− 2.2Hz, 1H), 7.53- mg, 23%) tetramethyl-1,3,2- (ES−), at 2.48 min, 7.64 (m,2H), 7.48 (s, dioxaborolan-2- 95.4% purity 2H), 7.84-7.93 (m, yl)phenol(76 mg, (method B). 2H), 10.44 (s, 1H). 0.299 mmol) (clii)3-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:1,2,4-triazin-6-yl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 6.55-6.56(m, 1H), (trifluoromethoxy)phe- (200 mg, 0.797 349 (M + H)⁺ (ES⁺);6.64-6.65 (m, 1H), nol (180 mg, 65%) mmol), 3-hydroxy-5- 347 (M − H)⁻(ES⁻), at 6.87-6.91 (m, 1H), (trifluoromethoxy)phe- 3.22 min, 100%7.31-7.53 (m, 7H), nylboronic acid (265 purity (method B). 10.15 (s,1H). mg, 1.195 mmol) (cliii) 5-(3-chloro-5- 6-bromo-5-(3-chloro- Mass(400 MHz, DMSO) δ: fluorophenyl)-6-(2,6- 5-fluorophenyl)- spectroscopy:m/z 2.37 (s, 6H), 7.02 (s, dimethylpyridin-4-yl)- 1,2,4-triazin-3-amine330(M + H)⁺ (ES⁺); 2H), 7.18 (ddd, J = 1,2,4-triazin-3-amine (90 mg,0.297 mmol), 328 (M − H)⁻ (ES⁻), at 9.3, 2.4, 1.4 Hz, 1H), (40 mg, 40%)2,6-dimethyl-4- 4.27 min, 98% purity 7.36 (t, J 1.4 Hz, 1H),(4,4,5,5-tetramethyl- (method B). 7.56-7.61 (m, 1H),1,3,2-dioxaborolan-2- 7.70 (s, 2H). yl)pyridine (79 mg, 0.341 mmol)(cliv) 5-(3,5- 6-bromo-5-(3,5- Mass (400 MHz, DMSO) δ:difluorophenyl)-6- difluorophenyl)-1,2,4- spectroscopy: m/z 2.37 (s,6H), 7.01 (s, (2,6-dimethylpyridin- triazin-3-amine (90 314 (M + H)⁺(ES⁺); 2H), 7.04-7.16 (m, 4-yl)-1,2,4-triazin-3- mg, 0.314 mmol), 312 (M− H)⁻ (ES⁻), at 2H), 7.38-7.44 (m, amine (50 mg, 49%) 2,6-dimethyl-4-3.95 min, 97% purity 1H), 7.70 (s, 2H). (4,4,5,5-tetramethyl- (method B)1,3,2-dioxaborolan-2- yl)pyridine (84 mg, 0.361 mmol) (clv) 5-(3,4-6-bromo-5-(3,4- Mass (400 MHz, DMSO) δ: difluorophenyl)-6-difluorophenyl)-1,2,4- spectroscopy: m/z 2.37 (s, 6H), 7.01 (s,(2,6-dimethylpyridin- triazin-3-amine (90 314(M + H)⁺ (ES⁺); 2H),7.15-7.23 (m, 4-yl)-1,2,4-triazin-3- mg, 0.314 mmol), 313 (M − H)⁻(ES⁻), at 1H), 7.42-7.56 (m, amine 2,6-dimethyl-4- 3.97 min, 99% purity2H), 7.65 (s, 2H). (4,4,5,5-tetramethyl- (method B).1,3,2-dioxaborolan-2- yl)pyridine (84 mg, 0.361 mmol) (clvi)5-(3-chloro-4- 6-bromo-5-(3-chloro- Mass (400 MHz, DMSO) δ:fluorophenyl)-6-(2,6- 4-fluorophenyl)- spectroscopy: m/z 2.37 (s, 6H),7.02 (s, dimethylpyridin-4-yl)- 1,2,4-triazin-3-amine 330(M + H)⁺ (ES⁺);2H), 7.29 (ddd, J 8.6, 1,2,4-triazin-3-amine (90 mg, 0.297 mmol), 328 (M− H)⁻ (ES⁻), at 4.7, 2.2 Hz, 1H), 7.40- (38 mg, 38%) 2,6-dimethyl-4- 4.2min, 97% purity 7.45 (m, 1H), 7.65 (4,4,5,5-tetramethyl- (method B). (s,2H), 7.73 (dd, J 1,3,2-dioxaborolan-2- 7.2, 2.2 Hz, 1H). yl)pyridine (79mg, 0.341 mmol) (clvii) 5-(4- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ:(difluoromethoxy)phe- (difluoromethoxy)phe- spectroscopy: m/z 2.35 (s,6H), 6.99 (s, nyl)-6-(2,6- nyl)-1,2,4-triazin-3- 344(M + H)⁺ (ES⁺); 2H),7.15-7.23 (m, dimethylpyridin-4-yl)- amine (90 mg, 0.284 342 (M − H)⁻(ES⁻), at 2H), 7.32 (t, ²J_(HF) 72 1,2,4-triazin-3-amine mmol),2,6-dimethyl- 3.93 min, 99% purity Hz, 1H), 7.43-7.49 (36 mg, 37%)4-(4,4,5,5- (method B). (m, 2H), 7.58 (s, 2H). tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (76 mg, 0.326 mmol) (clviii) 6-(2,6-6-bromo-5-(3- Mass (400 MHz, DMSO) δ: dimethylpyridin-4-yl)-fluorophenyl)-1,2,4- spectroscopy: m/z 2.36 (s, 6H), 7.02 (s,5-(3-fluorophenyl)- triazin-3-amine (90 295.0 (M − H)⁻ (ES⁻), 2H), 7.17(d, J 7.7 1,2,4-triazin-3-amine mg, 0.334 mmol) and at 3.82 min, 98.1%Hz, 1H), 7.25-7.36 (42 mg, 41%) 2,6-dimethyl-4- purity (method B). (m,2H), 7.38-7.45 (4,4,5,5-tetramethyl- (m, 1H), 7.66 (s, 2H).1,3,2-dioxaborolan-2- yl)pyridine (78 mg, 0.334 mmol) (clix)5-(4-chlorophenyl)-6- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ:(2,6-dimethylpyridin- chlorophenyl)-1,2,4- spectroscopy: m/z 2.39 (s,6H), 7.07 (s, 4-yl)-1,2,4-triazin-3- triazin-3-amine (90 312.7/314.7(M + H)⁺ 2H), 7.41-7.51 (m, amine (33 mg, 34%) mg, 0.315 mmol) and(ES⁺); 310.9/312.9 4H), 7.67 (s, 2H). 2,6-dimethyl-4- (M − H)⁻ (ES⁻), at(4,4,5,5-tetramethyl- 4.17 min, 100% 1,3,2-dioxaborolan-2- purity(method B). yl)pyridine (73.5 mg, 0.315 mmol) (clx) 4-(3-amino-6-(2,6-4-(3-amino-6-bromo- Mass (400 MHz, DMSO) δ: dimethylpyridin-4-yl)-1,2,4-triazin-5- spectroscopy: m/z 2.36 (s, 6H), 7.01 (s,1,2,4-triazin-5- yl)benzonitrile (90 303.8 (M + H)⁺ 2H), 7.55-7.64 (m,yl)benzonitrile (27 mg, 0.326 mmol) and (ES⁺); 302.0 (M − H)⁻ 2H), 7.73(s, 2H), mg, 27%) 2,6-dimethyl-4- (ES⁻), at 3.47 min, 7.85-7.95 (m, 2H).(4,4,5,5-tetramethyl- 98.5% purity 1,3,2-dioxaborolan-2- (method B).yl)pyridine (76 mg, 0.326 mmol) (clxi) 5-(3-chlorophenyl)-6-6-bromo-5-(3- Mass (400 MHz, DMSO) δ: (2,6-dimethylpyridin-chlorophenyl)-1,2,4- spectroscopy: m/z 2.35 (s, 6H), 7.00 (s,4-yl)-1,2,4-triazin-3- triazin-3-amine (90 312.7/314.7 (M + H)⁺ 2H),7.22-7.25 (m, amine (31 mg, 32%) mg, 0.315 mmol) and (ES⁺); 310.9/312.91H), 7.37 (dd, J 11.9, 2,6-dimethyl-4- (M − H)⁻ (ES⁻), at 4.2 Hz, 1H),7.51- (4,4,5,5-tetramethyl- 4.10 min, 100% 7.60 (m, 2H), 7.65 (s,1,3,2-dioxaborolan-2- purity (method B). 2H). yl)pyridine (73.5 mg,0.315 mmol) (clxii) 6-(2,6- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ:dimethylpyridin-4-yl)- (methoxymethyl)phe- spectroscopy: m/z 2.36 (s,6H), 3.28 (s, 5-(4- nyl)-1,2,4-triazin-3- 322.7 (M + H)⁺ 3H), 4.44 (s,2H), (methoxymethyl)phe- amine (90 mg, 0.305 (ES⁺); 320.9 (M − H)⁻ 7.03(s, 2H), 7.31- nyl)-1,2,4-triazin-3- mmol) and 2,6- (ES⁻), at 3.72 min,7.34 (m, 2H), 7.37- amine (32 mg, 32%) dimethyl-4-(4,4,5,5- 98.5% purity7.43 (m, 2H), 7.62 (s, tetramethyl-1,3,2- (method B). 2H).dioxaboralan-2- yl)pyridine (71.1 mg, 0.305 mmol) (clxiii)4-(3-amino-6-(3- 4-(3-amino-6-bromo- Mass (400 MHz, DMSO) δ:chloro-4-hydroxy-5- 1,2,4-triazin-5- spectroscopy: m/z 3.60 (s, 3H),6.81 (d, methoxyphenyl)- yl)benzonitrile (75 (Cl) 354.2/356.0 J 2.0 Hz,1H), 6.92 1,2,4-triazin-5- mg, 0.272 mmol) and (M + H)⁺ (ES⁺); (d, J 2.0Hz, 1H), yl)benzonitrile (10 2-chloro-6-methoxy- 352.1/354.0 (M − H)⁻7.45 (s, 2H), 7.56- gm, 10%) 4-(4,4,5,5- (ES⁻), at 2.56 min, 7.64 (m,2H), 7.84- tetramethyl-1,3,2- 94.6% purity 7.93 (m, 2H), 9.67 (s,dioxaborolan-2- (method B). 1H). yl)phenol (85 mg, 0.299 mmol) (clxiv)5-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:1,2,4-triazin-6-yl)-2- 1,2,4-triazin-3-amine spectroscopy: m/z 6.64 (dd,J = 8.2, 2.0 chlorophenol (43 mg, (90 mg, 0.358 mmol), 299, 301 (M + H)⁺Hz, 1H), 7.07 (d, J = 40%) 4-chloro-3- (ES⁺); 297, 299 (M − 2.0 Hz, 1H),7.23 (d, hydroxyphenylboronic H)⁻ (ES⁻), at J = 8.2 Hz, 1H), 7.34- acid(61.8 mg, 2.55 min, 99% purity 7.47 (m, 7H), 10.26 0.358 mmol) (methodB). (s, 1H). (clxv) 6-[2-chloro-6- 6-bromo-5-(3,4- Mass (400 MHz DMSO)(trifluoromethyl)pyridin- difluorophenyl)-1,2,4- spectroscopy: m/z δ:7.25-7.32 (m, 1H), 4-yl]-5-(3,4- triazin-3-amine (115 387.84/389.777.48-7.57 (q, 1H), difluorophenyl)-1,2,4- mg, 0.40 mmol) [M + H]⁺(ES)⁺7.58-7.66 (m, 1H), triazin-3-amine and 2-chloro-4- 99.70% at 4.60 mnin7.78(s, 1H), 7.82 (s, (20 mg, 13%) (4,4,5,5-tetramethyl- (method B).1H), 7.93-7.99 (bs, 1,3,2-dioxaborolan-2- 2H) yl)-6-(trifluoromethyl)pyri- dine (129 mg, 0.421 mmol) (clxvi) 6-[2-chloro-6-6-bromo-5-(3,5- Mass (400 MHz DMSO) (trifluoromethyl)pyridin-difluorophenyl)-1,2,4- spectroscopy: m/z δ: 7.20-7.25 (m, 2H),4-yl]-5-(3,5- triazin-3-amine (115 387.87/389.78 7.46-7.51 (m, 1H),difluorophenyl)-1,2,4- mg, 0.40 mmol) [M + H]+ (ES)⁺ 7.77 (s, 1H), 7.81(s, triazin-3-amine and 2-chloro-4- 99.17% at 4.59 min 1H), 8.00 (bs,2H) (26 mg, 17%) (4,4,5,5-tetramethyl- (method B). 1,3,2-dioxaborolan-2-yl)-6- (trifluoromethyl)pyridine (129 mg, 0.421 mmol) (clxvii)6-[2-(ethylamino)-6- 6-bromo-5-phenyl- Mass (400 MHz DMSO) δ:methylpyridin-4-yl]-5- 1,2,4-triazin-3-amine spectroscopy: m/z 1.03 (t,3H), 2.18 (s, phenyl-1,2,4-triazin- and 2-ethylamino-4- 307.1 3H), 3.94(s, 2H), 3-amine (6 mg, (4,4,5,5-tetramethyl- [M + H]+ (ES)⁺ 6.28 (s,1H), 6.34 (s, 0.2%) 1,3,2-dioxaborolan-2- 93.7% at 1.024 min 1H)7.37-7.50 (m, yl)-6-methylpyridine (method B). 5H). used crude fromborylation step) (clxviii) 6-[2-chloro-6- 6-bromo-5-(3- Mass (400 MHz,DMSO) δ: (trifluoromethyl)pyridin- fluorophenyl)-1,2,4- spectroscopy:m/z 7.24 (d, J7.5 Hz, 1 4-yl]-5-(3- triazin-3-amine 370/372 (M + H)⁺ H),7.33-7.43 (m, 2 fluorophenyl)-1,2,4- (108 mg, 0.40 mmol) (ES⁺); 368/370(M − H), 7.43-7.53 (m, 1 triazin-3-amine and 2-chloro-4- H)⁻ (ES⁻), at3.83 H), 7.76 (s, 1 H), 7.79 (16 mg, 11%) (4,4,5,5-tetramethyl- min, (s,1 H), 7.96 (bs, 2 1,3,2-dioxaborolan-2- 100% (method C). H). yl)-6-(trifluoromethyl)pyridine (129 mg, 0.42 mmol) (clxix) 6-[2-chloro-6-6-bromo-5-(4- Mass (400 MHz, DMSO) δ: (trifluoromethyl)pyridin-fluorophenyl)-1,2,4- spectroscopy: m/z 7.23-7.41 (m, 2 H), 4-yl]-5-(4-triazin-3-amine 370/372 (M + H)⁺ 7.46-7.65 (m, 2 H),fluorophenyl)-1,2,4- (108 mg, 0.40 mmol) (ES⁺); 368/370 (M − 7.76 (s, 1H), 7.79 (1 triazin-3-amine and 2-chloro-4- H)⁻ (ES⁻), at 3.84 H, s),7.90 (bs, 2 H). (13 mg, 9%) (4,4,5,5-tetramethyl- min,1,3,2-dioxaborolan-2- 100% (method C). yl)-6- (trifluoromethyl)pyridine(129 mg, 0.42 mmol) (clxx) 6-{2- 6-bromo-5-phenyl- Mass (400 MHz, DMSO)δ: [ethyl(methyl)amino]- 1,2,4-triazin-3-amine spectroscopy: m/z 0.86(t, J8 Hz, 3H) 6-methylpyridin-4-yl}- (126 mg, 0.5 mmol) 321 (M + H)⁺(ES⁺), 2.25 (s, 3 H) 2.81 (s, 5-phenyl-1,2,4- and 2- at 3.88 min, 3 H)4.11 (q, J8 Hz, 2 triazin-3-amine (16 ethyl(methyl)amino- 100% (methodC). H) 6.17 (s, 1 H) 6.49 mg, 10%) 4-(4,4,5,5- (s, 1 H) 7.32-7.47tetramethyl-1,3,2- (m, 5 H) 7.50 (bs, 2 dioxaborolan-2-yl)-6- H).methylpyridine (276 mg, crude) (clxxi) 6-[2-(dimethylamino)-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 6-methylpyridin-4-yl]-1,2,4-triazin-3-amine spectroscopy: m/z 2.24 (s, 3 H) 2.86 (s,5-phenyl-1,2,4- (126 mg, 0.5 mmol) 307 (M + H)⁺ (ES⁺), 6 H) 6.25 (s, 1H) triazin-3-amine and crude 2- at 3.43 min, >99% 6.46 (s, 1 H) 7.34-(13 mg, 8%) dimethylamino-4- (method C). 7.47 (m, 5 H) 7.47-(4,4,5,5-tetramethyl- 7.57 (m, 2 H). 1,3,2-dioxaborolan-2-yl)-6-methylpyridine (234 mg, crude) (clxxii) 1-[6-(2,6-d₆-6-bromo-5-phenyl- Mass (400 MHz, CDCl₃) δ: dimethylpyridin-4-yl)-1,2,4-triazin-3-amine spectroscopy: m/z 5.49 (s, 2H), 7.02 (s,5-phenyl-1,2,4- (310 mg, 1.24 mmol) 284.1 (M + H)⁺ (ES⁺) 2H), 7.33-7.39(m, triazin-3-amine and 1-[6-(2,6-d₆- at 2.48 min, 100% 2H), 7.43-7.49(m, (13.3 mg, 4%) dimethylpyridin-4-yl)- (method C). 3H).5-phenyl-1,2,4- triazin-3-amine (crude, 1.17 g) (clxxiii)6-[2-d₃-methyl-6- 6-bromo-5-phenyl- Mass (400 MHz, CDCl₃) δ:(trifluoromethyl)pyridin- 1,2,4-triazin-3-amine spectroscopy: m/z 5.57(s, 2H), 7.37- 4-yl]-5-phenyl- (178 mg, 0.71 mmol) 335.1 (M + H)⁺ 7.52(m, 7H). 1,2,4-triazin-3-amine and 2-(d₃)methyl-4- (ES⁺); 333.1 (M − H)⁻(28.5 mg, 12%) (4,4,5,5-tetramethyl- (ES⁻) at 3.56 min,1,3,2-dioxaborolan-2- 100% (method C). yl)-6- (trifluoromethyl)pyridine(226 mg, 0.78 mmol) (clxxiv) 5-(4-fluorophenyl)-6- 6-bromo-5-(4- Mass(400 MHz, CDCl₃) δ: [2-d₃-methyl-6- fluorophenyl)-1,2,4- spectroscopy:m/z 5.57 (s, 2H), 7.06- (trifluoromethyl)pyridin- triazin-3-amine 353.1(M + H)⁺ 7.12 (m, 2H), 7.45- 4-yl]-1,2,4-triazin- (189 mg, 0.70 mmol)(ES⁺); 351.1 (M − H)⁻ 7.50 (m, 3H), 7.51- 3-amine (93.3 mg, and2-(d₃)methyl-4- (ES⁻) at 3.68 min, 7.53 (m, 1H). 38%)(4,4,5,5-tetramethyl- 100% (method C). 1,3,2-dioxaborolan-2- yl)-6-(trifluoromethyl)pyridine (225 mg, 0.78 mmol) (clxxv) 6-(2,6-6-bromo-5-(2- Mass (400 MHz, DMSO), δ: dimethylpyridin-4-yl)-fluoropheny)-1,2,4- spectroscopy: m/z 2.31 (s, 6H), 6.93 (s,5-(2-fluorophenyl)- triazin-3-amine (50 296.0 (M + H)⁺ 2H), 7.18 (t, J7.8, 1,2,4-triazin-3-amine mg, 0.19 mmol) and (ES⁺), at 2.20 min, 1H),7.37 (t, J 6.5, (32 mg, 57%) 2,6-dimethyl-4- 100% (method C). 1H),7.54-7.66 (m, (4,4,5,5-tetramethyl- 6H) 1,3,2-dioxaborolan-2-yl)-pyridine (68 mg, 0.29 mmol) (clxxvi) 6-(2-chloro-6- 6-bromo-5-(2-Mass (400 Mhz, DMSO) methylpyridin-4-yl)-5- fluoropheny)-1,2,4-spectroscopy: m/z δ: 2.31 (s, 3H), 7.06 (2-fluorophenyl)-triazin-3-amine (50 315.9 (M + H)⁺ (s, 1H). 7.21 (t, J 7.8,1,2,4-triazin-3-amine mg, 0.19 mmol) and (ES⁺), at 2.66 min, 1H), 7.27(s, 1H), (21 mg, 35%) 2-chloro-4-(4,4,5,5- 100% (method C). 7.40 (t, J6.5, 1H), tetramethyl-1,3,2- 7.56-7.63 (m, dioxaborolan-2-yl)-6- 1H),7.64-7.69 (m, methylpyridine (74 1H), 7.80-7.90 (bs, mg, 0.29 mmol) 2H)(clxxvii) 6-(2,6- 6-bromo-5-(4- Mass (400 MHz, DMSO)dimethylpyridin-4-yl)- methoxypheny)- spectroscopy: m/z δ: 2.37 (s, 6H),3.78 5-(4-methoxyphenyl)- 1,2,4-triazin-3-amine 308.0 (M + H)⁺ (s, 3H),6.95 (d, J 9.0, 1,2,4-triazin-3-amine (50 mg, 0.18 mmol) (ES⁺), at 2.31min, 2H), 7.02 (s, 2H), (20 mg, 36%) and 2,6-dimethyl-4- 100% (methodC). 7.39 (d, J 9.0, 2H), (4,4,5,5-tetramethyl- 7.45-7.55 (bs, 2H)1,3,2-dioxaborolan-2- yl)-pyridine (63 mg, 0.27 mmol) (clxxviii)6-(2-chloro-6- 6-bromo-5-(4- Mass (400 MHz, DMSO) methylpyridin-4-yl)-5-methoxypheny)- spectroscopy: m/z δ: 2.42 (s, 3H), 3.80(4-methoxyphenyl)- 1,2,4-triazin-3-amine 328.0 (M + H)⁺ (s, 3H) 6.98 (d,J 8.8, 1,2,4-triazin-3-amine (50 mg, 0.18 mmol) (ES⁺), at 2.72 min, 2H),7.18 (s, 1H), (10 mg, 17%) and 2-chloro-4- 100% (method C). 7.31 (s,1H), 7.41 (d, (4,4,5,5-tetramethyl- J 8.8, 2H), 7.37-7.431,3,2-dioxaborolan-2- (s, 2H) yl)-6-methylpyridine (68 mg, 0.27 mmol)(clxxix) 6-[2-(difluoromethyl)- 6-bromo-5-phenyl- Mass (400 MHz, DMSO)6-methylpyridin-4-yl]- 1,2,4-triazin-3-amine spectroscopy: m/z δ: 2.46(s, 3H), 6.83 5-phenyl-1,2,4- (100 mg, 0.40 mmol) 314.1 (M + H)⁺ (t, J55.0, 1H), 7.33 triazin-3-amine (42 and (2- (ES⁺), at 1.38 min, (s, 1H),7.38-7.45 (m, mg, 32%) (difluoromethyl)-4- 100% (method A). 5H),7.47-7.52 (m, (4,4,5,5-tetramethyl- 1H), 7.62-7.75 (bs,1,3,2-dioxaborolan-2- 2H) yl)-6-methylpyridine (108 mg, 0.40 mmol)(clxxx) 6-[2-chloro-6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO)(difluoromethyl)pyridin- 1,2,4-triazin-3-amine spectroscopy: m/z δ: 6.94(t, J 54.5, 1H), 4-yl]-5-phenyl- (100 mg, 0.40 mmol) 333.9 (M + H)⁺7.41-7.48(m, 4H), 1,2,4-triazin-3-amine and 2-chloro-4- (ES⁺), at 1.56min, 7.50-7.56 (m, 1H), (27 mg, 20%) (4,4,5,5-tetramethyl- 100% (methodC). 7.57 (s, 1H), 7.62 (s, 1,3,2-dioxaborolan-2- 1H)yl)-6-(difluoromethyl)- pyridine (151 mg, 0.52 mmol) (clxxxi)6-[2-chloro-6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO)(fluoromethyl)pyridin- 1,2,4-triazin-3-amine spectroscopy: m/z δ: 5.43(d, J 46.4, 2H), 4-yl]-5-phenyl-1,2,4- (100 mg, 0.40 mmol) 316.0 (M +H)⁺ 7.33 (s, 1H), 7.41- triazin-3-amine (13 and 2-chloro-4- (ES⁺), at3.12 min, 7.46 (m, 5H), 7.47- mg, 10%) (4,4,5,5-tetramethyl- 100%(method C). 7.53 (m, 3H) 1,3,2-dioxaborolan-2- yl)-6-(fluoromethyl)-pyridine (141 mg, 0.52 mmol) (clxxxii) 6-[2-(difluoromethyl)-6-bromo-5-(4- Mass (400 MHz, DMSO) 6-methylpyridin-4-yl]-fluorophenyl)-1,2,4- spectroscopy: m/z δ: 2.49(s, 3H), 6.825-(4-fluorophenyl)- triazin-3-amine (100 332.0 (M + H)⁺ (t, J 55.0 Hz,1H), 1,2,4-triazin-3-amine mg, 0.37 mmol) and (ES⁺), at 1.42 min,7.19-7.31 (m, 1H), (32 mg, 26%) (2-(difluoromethyl-4- 100% (method A).7.36 (s, 1H), 7.44 (s, (4,4,5,5-tetramethyl- 1H), 7.46-7.52 (m,1,3,2-dioxaborolan-2- 2H), 7.54-7.58 (, 2H) yl)-6-methylpyridine (110mg, 0.41 mmol) (clxxxiii) 6-[2,6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO)δ: bis(fluoromethyl)pyri- 1,2,4-triazin-3-amine spectroscopy: m/z 5.43(d, J 46.9 Hz, dine-4-yl]-5-phenyl- (100 mg, 0.40 mmol) 314.0 (M + H)⁺4H), 7.38-7.45 (m, 1,2,4-triazin-3-amine and 2,6-bis- (ES⁺), at 1.33min, 6H), 7.47-7.51 (m, (10 mg, 8%) (fluoromethyl-4- 95% (method A).1H), 7.65-7.75(bs, (4,4,5,5-tetramethyl- 2H). 1,3,2-dioxaborolan-2-yl)-6-methylpyridine (140 mg, 0.52 mmol) (clxxxiv)6-[2-(fluoromethyl)-6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO)methylpyridin-4-yl]-5- 1,2,4-triazin-3-amine spectroscopy: m/z δ:2.40(s, 3H), 5.37 phenyl-1,2,4-triazin- (100 mg, 0.40 mmol) 296.0 (M +H)⁺ (d, J 46.9 Hz, 2H), 3-amine (10 mg, 8%) and (2-(fluoromethyl- (ES⁺),at 2.58 min, 7.20 (s, 2H), 7.38- 4-(4,4,5,5- 100% (method C). 7.45 (m,4H), 7.46- tetramethyl-1,3,2- 7.51 (m, 1H), 7.60- dioxaborolan-2-yl)-6-7.72 (bs, 2H) methylpyridine (151 mg, 0.60 mmol) (clxxxv) 6-(2-chloro-6-6-bromo-5-(2,5- Mass (400 MHz, DMSO) δ: methylpyridin-4-yl)-5-difluorophenyl)-1,2,4- spectroscopy: m/z 2.40 (s, 3H), 7.12 (s,(2,5-difluorophenyl)- triazin-3-amine (115 334.0 (M + H)⁺ 1H), 7.25-7.32(m, 1,2,4-triazin-3-amine mg, 0.40 mmol) and (ES+); at 2.87 min, 2H),7.42-7.49 (m, (24 mg, 18%) 2-chloro-4-(4,4,5,5- 95% (method C). 1H),7.51-7.56 (m, tetramethyl-1,3,2- 1H), 7.89 (br s, 2H).dioxaborolan-2-yl)-6- methylpyridine(129 mg, 0.42 mmol) (clxxxvi)6-[2-chloro-6- 6-bromo-5-(2- Mass (400 MHz, DMSO) δ:(trifluoromethyl)pyridin- fluorophenyl)-1,2,4- spectroscopy: m/z7.20-7.26 (m, 1H), 4-yl]-5-(2- triazin-3-amine (108 368.1(M + H)⁺ (ES+),7.38-7.45 (m, 1H), fluorophenyl)-1,2,4- mg, 0.40 mmol) and 370 (M − H)⁻(ES−); 7.56-7.74 (m, 3H), triazin-3-amine 2-chloro-4-(4,4,5,5- at 3.85min, 95% 7.78 (s, 1H). (18 mg, 12%) tetramethyl-1,3,2- (method C).dioxaborolan-2-yl)-6- (trifluoromethyl)pyridine (129 mg, 0.42 mmol)(clxxxvii) 6-[2-chloro-6- 6-bromo-5-(2,5- Mass (400 MHz, DMSO) δ:(trifluoromethyl)pyridin- difluorophenyl)-1,2,4- spectroscopy: m/z7.27-7.35 (m, 1H), 4-yl]-5-(2,5- triazin-3-amine (115 386.1(M − H)⁻(ES−); 7.45-7.52 (m, 1H), difluorophenyl)-1,2,4- mg, 0.40 mmol) and at3.93 min, 95% 7.52-7.58 (m, 1H), triazin-3-amine 2-chloro-4-(4,4,5,5-(method C). 7.79 (s, 1H), 7.82 (s, (17 mg, 11%) tetramethyl-1,3,2- 1H),8.08 (bs, 2H). dioxaborolan-2-yl)-6- (trifluoromethyl)pyridine (129 mg,0.42 mmol) (clxxxviii) 6-[2-cyclopropyl-6- 6-bromo-5-phenyl- Mass (400MHz, DMSO) δ: (trifluoromethyl)pyridin- 1,2,4-triazin-3-aminespectroscopy: m/z 0.79-0.84 (m, 2H), 4-yl]-5-phenyl- (50 mg, 0.20 mmol)358 (M + H)⁺ (ES+); 0.97-1.03 (m, 2H), 1,2,4-triazin-3-amine and2-cyclopropyl-4- at 4.43 min, 100% 2.10-2.17 (m, 1H), (20 mg, 26%)(4,4,5,5-tetramethyl- (method C). 7.39-7.46 (m, 6H),1,3,2-dioxaborolan-2- 7.47-7.53 (m, 1H), yl)-6- 7.61 (bs, 2H).(trifluoromethyl)pyridine (66 mg, 0.21 mmol) (clxxxix) 6-[2-ethyl-6-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl)pyridin-1,2,4-triazin-3-amine spectroscopy: m/z 1.10 (t, 3H, J8.0 Hz),4-yl]-5-phenyl- (50 mg, 0.20 mmol) 346.0 (M + H)⁺ 2.75 (q, 2H, J 8.0),1,2,4-triazin-3-amine and 2-ethyl-4- (ES+), 344.2 (M − H)⁻ 7.40-7.44 (m,4H), (37 mg, 55%) (4,4,5,5-tetramethyl- (ES−) at 4.08 min, 7.47-7.53 (m,2H). 1,3,2-dioxaborolan-2- 100% (method C). 7.57 (s, H), 7.76 (bs,yl)-6- 2H). (trifluoromethyl)pyridine (63 mg, 0.21 mmol) (cxc)6-(2-cyclopropyl-6- 6-(2-chloro-6- Mass (400 MHz, DMSO) δ:methylpyridin-4-yl)-5- methylpyridin-4-yl)-5- spectroscopy: m/z0.70-0.76 (m, 2H), phenyl-1,2,4-triazin- phenyl-1,2,4-triazin- 304.1(M + H)⁺ 0.82-0.89 (m, 2H), 3-amine 3-amine (70 mg, 0.23 (ES+); at 3.22min, 1.88-1.97 (m, 1H), (32 mg, 46%) mmol) and 100% (method C). 2.32 (s,3H), 6.88 (s, cyclopropyltrifluoro- 1H), 6.97 (s, 1H), borate potassiumsalt 7.38-7.43 (m, 4H), (340 mg, 2.30 mmol) 7.45-7.52 (m, 1H), 7.54-7.62(bs, 2H). (cxci) 5-(2-fluorophenyl)-6- 6-bromo-5-(2- Mass (400 MHz,DMSO) δ: [2-methyl-6- fluorophenyl)-1,2,4- spectroscopy: m/z 2.51 (s,3H), 7.17- (trifluoromethyl)pyridin- triazin-3-amine (108 350.0 (M + H)⁺(ES⁺) 7.22 (m, 1H), 7.38- 4-yl]-1,2,4-triazin- mg, 0.40 mmol) and at3.30 min, 7.42 (m, 2H), 7.56- 3-amine (65.3 mg, 2-methyl-6- ~98% (methodC). 7.63 (m, 2H), 7.67- 47%) trifluoromethyl-4- 7.71 (m, 1H), 7.88(4,4,5,5-tetramethyl- (bs, 2H). 1,3,2-dioxaborolan-2- yl)pyridine (121mg, 0.42 mmol) (cxcii) 5-(3-fluorophenyl)-6- 6-bromo-5-(3- Mass (400MHz, CDCl₃) [2-methyl-6- fluorophenyl)-1,2,4- spectroscopy: m/z δ: 2.61(s, 3H), 5.62 (trifluoromethyl)pyridin- triazin-3-amine (108 350.0 (M +H)⁺ (ES⁺) (bs, 2H), 7.10- 4-yl]-1,2,4-triazin- mg, 0.40 mmol) and at3.24 min, 7.20 (m, 1H), 7.18- 3-amine (72.8 mg, 2-methyl-6- ~98% (methodC). 7.23 (m, 1H), 7.28- 52%) trifluoromethyl-4- 7.35 (m, 2H), 7.48-(4,4,5,5-tetramethyl- 7.50 (m, 2H). 1,3,2-dioxaborolan-2- yl)pyridine(121 mg, 0.42 mmol) (cxciii) 5-(4-fluorophenyl)-6- 6-bromo-5-(4- Mass(400 MHz, CDCl₃) [2-methyl-6- fluorophenyl)-1,2,4- spectroscopy: m/z δ:2.61 (s, 3H), 5.58 (trifluoromethyl)pyridin- triazin-3-amine (108 350.0(M + H)⁺ (ES⁺) (bs, 2H), 7.07- 4-yl]-1,2,4-triazin- mg, 0.40 mmol) andat 3.26 min, 7.11 (m, 2H), 7.46- 3-amine (78.9 mg, 2-methyl-6- 98%(method C). 7.52 (m, 4H). 56%) trifluoromethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (121 mg, 0.42 mmol) (cxciv) 5-(2,5-6-bromo-5-(2,5- Mass (400 MHz, DMSO) δ: difluorophenyl)-6-[2-difluorophenyl)-1,2,4- spectroscopy: m/z 2.53 (s, 3H), 7.25- methyl-6-triazin-3-amine (115 368.0 (M + H)⁺ (ES⁺) 7.30 (m, 1H), 7.44-(trifluoromethyl)pyridin- mg, 0.40 mmol) and at 3.38 min, 7.50 (m, 2H),7.55- 4-yl]-1,2,4-triazin- 2-methyl-6- 98% (method C). 7.59 (m, 1H),7.65 (s, 3-amine (61.7 mg, trifluoromethyl-4- 1H), 7.95 (bs, 2H). 42%)(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)pyridine (121 mg, 0.42mmol) (cxcv) 5-(3,4- 6-bromo-5-(3,4- Mass (400 MHz, DMSO) δ:difluorophenyl)-6-[2- difluorophenyl)-1,2,4- spectroscopy: m/z 2.54 (s,3H), 7.22- methyl-6- triazin-3-amine (115 368.0 (M + H)⁺ (ES⁺) 7.24 (m,1H), 7.46- (trifluoromethyl)pyridin- mg, 0.40 mmol) and at 4.34 min,7.57 (m, 3H), 7.62 (s, 4-yl]-1,2,4-triazin- 2-methyl-6- 100% (method B).1H), 7.81 (bs, 2H). 3-amine (40.0 mg, trifluoromethyl-4- 27%)(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)pyridine (121 mg, 0.42mmol) (cxcvi) 5-(3,5- 6-bromo-5-(3,5- Mass (400 MHz, DMSO) δ:difluorophenyl)-6-[2- difluorophenyl)-1,2,4- spectroscopy: m/z 2.54 (s,3H), 7.16- methyl-6- triazin-3-amine (115 368.0 (M + H)⁺ (ES⁺) 7.19 (m,2H), 7.42- (trifluoromethyl)pyridin- mg, 0.40 mmol) and at 3.53 min,7.49 (m, 2H), 7.64 (s, 4-yl]-1,2,4-triazin- 2-methyl-6- ~98% (254 nm).1H), 7.81 (bs, 2H). 3-amine (73.3 mg, trifluoromethyl-4- 49%)(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)pyridine (121 mg, 0.42mmol) (cxcvii) 6-[2-(azetidin-1-yl)-6- 6-bromo-5-(4- Mass (400 MHz,CDCl₃) (trifluoromethyl)pyridin- fluorophenyl)-1,2,4- spectroscopy: m/zδ: 2.27-2.35 4-yl]-5-(4- triazin-3-amine (150 391.0 (M + H)⁺ (ES⁺)(quint., J 7.4, 2H), fluorophenyl)-1,2,4- mg, 0.56 mmol) and at 3.89min, 3.89 (t, J 7.4, 4H), triazin-3-amine 2-(azetid-1-yl)-6- ~98%(method C). 5.52 (bs, 2H), 6.54 (40.2 mg, 18%) trifluoromethyl-4- (s,1H), 6.83 (s, 1H), (4,4,5,5-tetramethyl- 7.06-7.10 (m, 2H),1,3,2-dioxaborolan-2- 7.49-7.53 (m, 2H). yl)pyridine (192 mg, 0.59 mmol)(cxcviii) 6-[2-methyl-6- 6-bromo-5-phenyl- Mass (400 MHz, CDCl₃)(morpholin-4- 1,2,4-triazin-3-amine spectroscopy: m/z δ: 2.33 (s, 3H),3.39- yl)pyridin-4-yl]-5- (251 mg, 1.0 mmol) 349.1 (M + H)⁺ (ES⁺) 3.42(m, 2H), 3.76- phenyl-1,2,4-triazin- and 2-methyl-6- at 1.16 min, 3.78(m, 2H), 5.49 3-amine (43.0 mg, (morpholin-4-yl)-4- ~95% (method B).(bs, 2H), 6.52 (s, 12%) (4,4,5,5-tetramethyl- 1H), 6.55 (s, 1H),1,3,2-dioxaborolan-2- 7.34-7.38 (m, 2H), yl)pyridine (320 mg, 7.43-7.45(m, 1H), 1.05 mmol) 7.50-7.52 (m, 2H). (cxcix) 6-(2-chloro-6-6-bromo-5-(4- Mass (400 MHz, DMSO) δ: methylpyridin-4-yl)-5-methylphenyl)-1,2,4- spectroscopy: m/z 1.18 (t, 3H), 2.40 (s,(4-ethylphenyl)-1,2,4- triazin-3-amine (94 324.2 (M − H)⁻ (ES−) 3H),2.64 (q, 2H), triazin-3-amine (6 mg, crude - assume at 2.16 min, 97%7.22 (s, 1H), 7.55 (m, mg, 6%) 0.17 mmol) and 2- (method B) 3H), 7.38(m, 2H) chloro-4-(4,4,5,5- (NH₂ not observed) tetramethyl-1,3,2-dioxaborolan-2-yl)-6- methylpyridine (128 mg, 0.506 mmol) (cc) 5-(2,5-6-bromo-5-(2,5- Mass (400 MHz, DMSO) δ: difluorophenyl)-6-difluorophenyl)- spectroscopy: m/z 2.34 (s, 6H), 6.98 (s,(2,6-dimethylpyridin- 1,2,4-triazin-3-amine 314.3 (M + H)⁺ (ES+) 2H),7.26 (m, 1H), 4-yl)-1,2,4-triazin-3- (90 mg, 0.314 mmol) at 0.97 min,100% 7.44 (m, 1H), 7.54 amine (12 mg, 12%) and 2,6-dimethyl-4- (methodB) (m, 1H), 1.78 (bs, 2H) (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine (110 mg, 0.47 mmol) (cci) 6-(2,6- 6-bromo-5-(4- Mass (400MHz, DMSO) δ: dimethylpyridin-4-yl)- methylphenyl)-1,2,4- spectroscopy:m/z 2.31 (s, 3H), 2.36 (s, 5-(4-methylphenyl)- triazin-3-amine (85 293.3(M + H)⁺ (ES+) 6H), 6.99 (s, 2H), 1,2,4-triazin-3-amine mg, 0.32 mmol)and at 1.06 min, 99% 7.20 (m, 2H), 7.33 (16 mg, 17%) 2,6-dimethyl-4-(method B) (m, 2H), 7.53 (bs, (4,4,5,5-tetramethyl- 2H).1,3,2-dioxaborolan-2- yl)pyridine (112 mg, 0.48 mmol) (ccii)6-[2-(difluoromethyl)- 6-bromo-5-(3- Mass (400 MHz, CDCl₃)6-methylpyridin-4-yl]- fluorophenyl)-1,2,4- spectroscopy: m/z δ: 2.51(s, 3H), 5.51 5-(3-fluorophenyl)- triazin-3-amine (70 332.3, M⁺ (ESI+)at (bs, 2H), 6.55 (t, 1H), 1,2,4-triazin-3-amine mg, 0.26 mmol) and 1.84min, 96% 7.13 (m, 1H), 7.29 (17 mg, 20%) (2-(difluoromethyl-4- (methodB). (m, 1H), 7.32 (m, 1H), (4,4,5,5-tetramethyl- 7.40 (s, 1H), 7.44 (s,1,3,2-dioxaborolan-2- 1H) yl)-6-methylpyridine (70 mg, 0.26 mmol)(cciii) 6-[2-(difluoromethyl)- 6-bromo-5-(3- Mass (400 MHz, CDCl₃)6-methylpyridin-4-yl]- fluorophenyl)-1,2,4- spectroscopy: m/z δ: 2.55(s, 3H), 5.54 5-(2-fluorophenyl)- triazin-3-amine (70 332.3, M⁺ (ESI+)at (bs, 2H), 6.51 (t, 1H), 1,2,4-triazin-3-amine mg, 0.26 mmol)and 1.80min, 96% 7.00 (m, 1H), 7.30 (s, (20 mg, 23%) (2-(difluoromethyl-4-(method B). 1H) 7.32 (m, 1H), (4,4,5,5-tetramethyl- 7.43 (s, 1H), 7.50(m, 1,3,2-dioxaborolan-2- 1H), 7.58 (m, 1H). yl)-6-methylpyridine (70mg, 0.26 mmol) (cciv) 6-(3,5- 6-bromo-5-(pyridin-2- HPLC purity: (400MHz, DMSO) δ: dichlorophenyl)-5- yl)-1,2,4-triazin-3- 98.56%; (268 nm).7.26 (m, 2H), 7.49 (pyridin-2-yl)-1,2,4- amine (0.25 g, 0.99 Mass (m,1H), 7.54 (m, 1H), triazin-3-amine (23 mmol) and 3,5- spectroscopy: 7.68(bs, 2H), 7.91 mg, 7%) dichlorophenylboronic (ESI +ve) 318.0 (m, 1H),8.00 (t, 1H), acid (0.20 g, 1.09 [M + H]⁺, 316.1 8.43 (d, 1H). mmol)[M + H]⁻. (ccv) 6-(3-chloro-5- 6-bromo-5-(pyridin-2- HPLC purity: (400MHz, DMSO) δ: methylphenyl)-5- yl)-1,2,4-triazin-3- 99.60%; (266 nm).2.22 (s, 3H), 6.99 (s, (pyridin-2-yl)-1,2,4- amine (0.20 g, 0.79 Mass1H), 7.07 (s, 1H), triazin-3-amine (12 mmol) and 3-chloro- spectroscopy:7.18 (s, 1H), 7.45- mg, 5%) 5-methylphenyl- (ESI +ve) 298.2 7.48 (m,1H), 7.56 boronic acid (0.175 [M + H]⁺. (bs, 2H), 7.79 (d, 1H), g, 1.03mmol) 7.94-7.98 (m, 1H), 8.44 (d, 1H). (ccvi) 6-[2-chloro-6-6-bromo-5-phenyl- HPLC purity: ¹H NMR: (400 MHz,(trifluoromethyl)pyridin- 1,2,4-triazin-3-amine 96.75% (272 nm) DMSO) δ:7.44 (m, 4-yl]-5-phenyl- (0.70 g, 2.8 mmol) Mass 5H), 7.69 (s, 1H),1,2,4-triazin-3-amine and 2-chloro-4- spectroscopy: 7.88 (s, 1H), 7.84(bs, (50 mg, 5%) (4,4,5,5-tetramethyl- (ESI +ve) 352.1 2H).1,3,2-dioxaborolan-2- [M + H]⁺. yl)-6- (trifluoromethyl)pyridine (1.02g, 3.34 mmol) (ccvii) 6-[2,6- 6-bromo-5-phenyl- HPLC purity: ¹H NMR:(400 MHz, bis(trifluoromethyl)pyr- 1,2,4-triazin-3-amine 98.90% (232 nm)DMSO) δ: 7.48 (m, idin-4-yl]-5-phenyl- (0.52 g, 2.07 mmol) Mass 5H),7.93 (bs, 2H), 1,2,4-triazin-3-amine and 2,6- spectroscopy: 8.03 (s,2H). (0.10 g, 13%) bis(trifluoromethyl)-4- (ESI +ve)(4,4,5,5-tetramethyl- 386.1[M + H]⁺, (ESI −ve) 1,3,2-dioxaborolan-2-384.2[M − H]⁻. yl)pyridine (1.0 g, 3.1 mmol) (ccviii) 6-[3-chloro-5-6-bromo-5-(pyridin-2- HPLC purity: (400 MHz, DMSO) δ:(trifluoromethyl)phe- yl)-1,2,4-triazin-3- 99.87%; (268 nm). 7.45-7.48(m, 2H), nyl]-5-(pyridin-2-yl)- amine (0.225 g, 0.89 Mass 7.65 (s, 1H),7.70 (bs, 1,2,4-triazin-3-amine mmol) and 3-chloro- spectroscopy: 2H),7.77 (s, 1H), (30 mg, 10%) 5-(trifluoromethyl)- (ESI +ve) 352.1 7.91 (m,1H), 8.0 (m, phenylboronic acid [M + H]⁺. 1H), 8.36 (d, 1H). (0.260 g,1.16 mmol) (ccix) 6-[2-methyl-6- 6-bromo-5-phenyl- HPLC purity: (400MHz, DMSO) δ: (trifluoromethyl)pyridin- 1,2,4-triazin-3-amine 98.81%(269 nm) 2.48 (s, 3H), 7.38 (m, 4-yl]-5-phenyl- (0.70 g, 2.78 mmol) Mass5H), 7.47 (s, 1H), 1,2,4-triazin-3-amine and 2-methyl-4- spectroscopy:7.58 (s, 1H), 7.73 (bs, (0.32 g, 35%) (4,4,5,5-tetramethyl- (ESI +ve)332.0 2H). 1,3,2-dioxaborolan-2- [M + H]⁺, (ESI −ve)yl)-6-trifluoromethyl- 330.2 [M − H]⁻. pyridine (1.2 g, 4.1 mmol) (ccx)6-(3,5- 6-bromo-5-(pyridin-2- HPLC purity: (400 MHz, DMSO) δ:dimethylphenyl)-5- yl)-1,2,4-triazin-3- 98.96%; (268 nm). 2.12 (s, 6H),6.81 (s, (pyridin-2-yl)-1,2,4- amine (0.20 g, 0.79 Mass 2H), 6.88 (s,1H), triazin-3-amine (16 mmol) and 3,5- spectroscopy: 7.40-7.43 (m, 3H),mg, 7%) dimethylphenylboronic (ESI +ve) 277.9 7.64-7.66 (m, 1H), acid(0.15 g, 1.02 [M + H]⁺. 7.89 (m, 1H), 8.43 mmol) (m, 1H). (ccxi) 6-[2-6-bromo-5-phenyl- HPLC purity: (400 MHz, DMSO) δ:(dimethylamino)pyridin- 1,2,4-triazin-3-amine 99.18% (272 nm) 2.97 (s,6H), 6.46 (m, 4-yl]-5-phenyl- (0.5 g, 1.99 mmol) Mass 1H), 6.56 (m, 1H),1,2,4-triazin-3-amine and 2- spectroscopy: 7.37-7.47 (m, 5H), (83 mg,33%) dimethylamino- (ESI +ve) 292.8 7.54 (bs, 2H), 7.99(4,4,5,5-tetramethyl- [M + H]⁺. (m, 1H). 1,3,2-dioxaborolan-2-yl)pyridine (0.98 g, 3.9 mmol) (ccxii) 6-(2-bromo-6- 6-bromo-5-phenyl-HPLC purity: (400 MHz, DMSO) δ: methylpyridin-4-yl)-5-1,2,4-triazin-3-amine 98.71% (272 nm) 2.38 (s, 3H), 7.25 (s,phenyl-1,2,4-triazin- (0.25 g, 0.90 mmol) Mass 1H), 7.30 (s, 1H),3-amine (76 mg, and 2-bromo-4- spectroscopy: 7.47 (m, 5H), 7.72 22%)(4,4,5,5-tetramethyl- (ESI +ve) 341.9 [M]⁺, (bs, 2H).1,3,2-dioxaborolan-2- 343.9 [M]⁺. yl)-6-methylpyridine (0.44 g, 1.4mmol) (ccxiii) 6-(2,6-dimethyl-1- 6-bromo-5-phenyl- HPLC purity: (400MHz, CDCl₃) δ: oxidopyridin-4-yl)-5- 1,2,4-triazin-3-amine 98.85% (294nm) 2.48 (s, 6H), 5.66 (bs, phenyl-1,2,4-triazin- (0.50 g, 1.99 mmol)Mass 2H), 7.24 (s, 1H), 3-amine (87 mg, and 2,6-dimethyl-4-spectroscopy: 7.28 (s, 1H), 7.49 (m, 15%) (4,4,5,5-tetramethyl- (ESI+ve) 293.7 2H), 7.52 (m, 3H). 1,3,2-dioxaborolan-2- [M + H] ⁺, (ESI −ve)yl)pyridine-N-oxide 292.0 [M − H]⁻. (0.74 g, 2.98 mmol) (ccxiv)4-(3-amino-5-phenyl- 6-bromo-5-phenyl- HPLC purity: (400 MHz, DMSO) δ:1,2,4-triazin-6-yl)-6- 1,2,4-triazin-3-amine 99.18% (272 nm) 2.48 (s,3H), 7.45- methylpyridine-2- (0.25 g, 0.99 mmol) Mass 7.52 (m, 5H), 7.61(s, carbonitrile (140 mg, and 2-cyano-4- spectroscopy: 1H), 7.63 (s,1H), 49%) (4,4,5,5-tetramethyl- (ESI +ve) 288.9 7.79 (bs, 2H).1,3,2-dioxaborolan-2- [M + H]⁺. yl)-6-methylpyridine (0.36 g, 1.4 mmol)(ccxv) 6-(3,5- 6-bromo-5-(pyridin-3- HPLC purity: (400 MHz, DMSO) δ:dichlorophenyl)-5- yl)-1,2,4-triazin-3- 98.66% (266 nm) 7.39 (m, 2H),7.42- (pyridin-3-yl)-1,2,4- amine (0.3 g, 1.19 Mass 7.46 (m, 1H), 7.62triazin-3-amine (3 mmol) and 3,5- spectroscopy: (m, 1H), 7.69 (bs, mg,1%) dichlorophenylboronic (ESI +ve) 317.9 2H), 7.82 (m, 1H), acid (0.22g, 1.19 [M + H]⁺. 315.9 8.59 (m, 1H), 8.63 mmol) [M + H]⁻ (m, 1H).(ccxvi) 6-(3-chloro-5- 6-bromo-5-(pyridin-3- HPLC purity: (400 MHz,DMSO) δ: methylphenyl)-5- yl)-1,2,4-triazin-3- 92.24% (218 nm) 2.25 (s,3H), 6.82 (s, (pyridin-3-yl)-1,2,4- amine (0.19 g, 0.75 Mass 1H),7.15-7.17 (m, triazin-3-amine (11 mmol) and 3-chloro- spectroscopy: 1H),7.27 (s, 1H), mg, 5%) 5- (ESI +ve) 297.9.0 7.40 (m, 1H), 7.59methylphenylboronic [M + H]⁺, 295.9 (bs, 2H), 7.77 (m, acid (0.166 g,0.98 [M + H]⁻ 1H), 8.56 (m, 1H), mmol) 8.61 (m, 1H). (ccxvii) 6-(3,5-6-bromo-5- HPLC purity: (400 MHz, DMSO) δ: dichlorophenyl)-5-(pyrimidin-2-yl)-1,2,4- 97.14% (210 nm) 7.21 (s, 2H), 7.58 (s,(pyrimidin-2-yl)-1,2,4- triazin-3-amine (0.5 Mass 1H), 7.65 (t, 1H),7.84 triazin-3-amine (40 g, 1.98 mmol) and spectroscopy: (bs, 2H), 8.93(d, 2H). mg, 6%) 3,5- (ESI +ve) 318.9 dichlorophenylboronic [M + H]⁺,316.9 acid (0.414 g, 2.18 [M + H]⁻. mmol) (ccxviii) 6-[3-chloro-5-6-bromo-5- HPLC purity: (400 MHz, DMSO) δ: (trifluoromethyl)phe-(pyrimidin-2-yl)-1,2,4- 93.30% (202 nm) 7.38 (s, 1H), 7.64 (m,nyl]-5-(pyrimidin-2-yl)- triazin-3-amine (0.50 Mass 2H), 7.86 (m, 3H),1,2,4-triazin-3-amine g, 1.98 mmol) and 3- spectroscopy: 8.91 (d, 2H).(0.130 g, 19%) chloro-5- (ESI +ve) 353.0 (trifluoromethyl) [M + H]⁺,351.0 phenylboronic acid [M + H]⁻. (0.488 g, 2.18 mmol) (ccxix)6-[2-bromo-6- 6-bromo-5-phenyl- HPLC purity: (400 MHz, DMSO) δ:(trifluoromethyl)pyridin- 1,2,4-triazin-3-amine 94.90% (272 nm) 7.47 (m,5H), 7.74 (s, 4-yl]-5-phenyl- (0.25 g, 0.9 mmol) Mass 1H), 7.84 (s, 1H),1,2,4-triazin-3-amine and 2-bromo-4- spectroscopy: 7.88 (bs, 2H). (30mg, 8%) (4,4,5,5-tetramethyl- (ESI +ve) 396.1 1,3,2-dioxaborolan-2- [M +H]⁺, 397.9 yl)-6- [M + H]⁺. (trifluoromethyl)pyridine (0.52 g, 1.48mmol) (ccxx) 6-[3-chloro-5- 6-bromo-5-(pyridin-3- HPLC purity: (400 MHz,DMSO) δ: (trifluoromethyl)phe- yl)-1,2,4-triazin-3- 91.22% (266 nm) 7.41(m, 1H), 7.62 (s, nyl]-5-(pyridin-3-yl)- amine (0.20 g, 0.79 Mass 1H),7.72 (bs, 2H), 1,2,4-triazin-3-amine mmol) and 3-chloro- spectroscopy:7.76-7.80 (m, 2H), (8 mg, 3%) 5- (ESI +ve) 351.8 7.87 (s, 1H), 8.58 (m,(trifluoromethyl)phe- [M + H]⁺, 349.9 1H), 8.62-8.64 (m, nylboronic acid(0.21 [M + H]⁻ 1H). g, 0.95 mmol) (ccxxi) 6-(3-chloro-5- 6-bromo-5- HPLCpurity: (400 MHz, DMSO) δ: methylphenyl)-5- (pyrimidin-2-yl)-1,2,4-95.27% (266 nm) 2.21 (3H, s), 6.98 (m, (pyrimidin-2-yl)-1,2,4-triazin-3-amine (0.5 Mass 2H), 7.21 (s, 1H), triazin-3-amine (130 g,1.98 mmol) and 3- spectroscopy: 7.62 (t, 1H), 7.74 (s, mg, 22%)chloro-5- (ESI +ve) 299.0 2H), 8.90 (d, 2H) methylphenylboronic [M +H]⁺, acid (0.650 g, 2.18 mmol)

The following compounds were prepared according to a modified version ofthe general procedure described for Example 1. In these cases, thereactions were run using palladium acetate (1.5 mol %), dppf (3.0 mol%), copper bromide (1.5 eq.), caesium carbonate (2.0 eq.) and DMF (0.8mL).

No. Product (yield) Prepared From LCMS NMR (ccxxii)6-(6-chloropyridin-2- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:yl)-5-phenyl-1,2,4- 1,2,4-triazin-3-amine spectroscopy: m/z 7.31-7.39(m, 4H), triazin-3-amine (7 (100 mg, 0.398 284.7 (M + H)⁺ 7.39-7.46 (m,1H), mg, 6%) mmol), 6- (ES⁺), at 3.75 min, 7.47 (dd, J = 8.0, 0.8chloropyridin-2- 99.2% purity Hz, 1H), 7.66 (s, 2H), ylboronic acid (141(method B). 7.77 (dd, J = 7.6, 0.8 mg, 0.896 mmol) Hz, 1H), 7.95 (t, J =7.8 Hz, 1H). (ccxxiii) 6-(4- 6-bromo-5-phenyl- Mass (400 MHz, CDCl₃) δ:cyclopropylpyridin-2- 1,2,4-triazin-3-amine spectroscopy: m/z 0.89-1.01(m, 4H), yl)-5-phenyl-1,2,4- (50 mg, 0.199 mmol), 290.6 (M + H)⁺1.97-2.06 (m, 1H), triazin-3-amine (3 and 4-cyclopropyl-2- (ES⁺); 288.9(M − H)⁻ 5.50 (s, 2H), 6.98 mg, 5% (4,4,5,5-tetramethyl- (ES⁻), at 3.93min, (dd, J = 5.2, 1.7 Hz, 1,3,2-dioxaborolan-2- 99.4% purity 1H),7.26-7.29 (m, yl)pyridine (110 mg, (method B). 1H), 7.33-7.41 (m, 0.448mmol), 2H), 7.43-7.50 (m, 3H), 8.35 (d, J = 4.8 Hz, 1H). (ccxxiv)5-phenyl-6-(6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:(trifluoromethyl)pyridin- 1,2,4-triazin-3-amine spectroscopy: m/z7.27-7.35 (m, 4H), 2-yl)-1,2,4-triazin- (100 mg, 0.398 318.6 (M + H)⁺7.36-7.44 (m, 1H), 3-amine (27 mg, mmol), 2-(4,4,5,5- (ES⁺); 316.9 (M −H)⁻ 7.69 (s, 2H), 7.84 29%) tetramethyl-1,3,2- (ES⁻), at 4.09 min, (dd,J 7.4, 1.3 Hz, dioxaborolan-2-yl)-6- 98.9% purity 1H), 8.11-8.23 (m,(trifluoromethyl)pyridine (method B). 2H). (245 mg, 0.896 mmol) (ccxxv)5-phenyl-6-(4- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:(trifluoromethyl)pyridin- 1,2,4-triazin-3-amine spectroscopy: m/z7.26-7.38 (m, 4H), 2-yl)-1,2,4-triazin- (100 mg, 0.398 318.7 (M + H)⁺7.38-7.45 (m, 1H), 3-amine (10 mg, 8%) mmol), 2-(4,4,5,5- (ES⁺); 316.9(M − H)⁻ 7.69 (s, 2H), 7.74 tetramethyl-1,3,2- (ES⁻), at 4.12 min, (dd,J 5.1, 1.1 Hz, dioxaborolan-2-yl)-4- 98.5% purity 1H), 8.18 (s, 1H),(trifluoromethyl)pyridine (method B). 8.63 (d, J 5.1 Hz, (245 mg, 0.8961H). mmol) (ccxxvi) 6-(6- 6-bromo-5-phenyl- Mass (400 MHz, CDCl₃) δ:cyclopropylpyridin-2- 1,2,4-triazin-3-amine spectroscopy: m/z 0.21-0.32(m, 2H), yl)-5-phenyl-1,2,4- (50 mg, 0.199 mmol), 290.3 (M + H)⁺0.55-0.64 (m, 2H), triazin-3-amine (2 2-cyclopropyl-6- (ES⁺), at 1.85min, 1.77 (tt, J 8.1, 4.7 mg, 3%) (4,4,5,5-tetramethyl- 98.4% purity Hz,1H), 5.41 (s, 2H), 1,3,2-dioxaborolan-2- (method B). 7.11 (dd, J 7.7,1.0 yl)pyridine (110 mg, Hz, 1H), 7.28-7.42 0.448 mmol) (m, 5H),7.61-7.68 (m, 1H), 7.75 (dd, J 7.7, 1.0 Hz, 1H). (ccxxvii)5-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, CDCl₃) δ:1,2,4-triazin-6- 1,2,4-triazin-3-amine spectroscopy: m/z 5.34 (s, 2H),7.42- yl)pyrazin-2-ol (2 mg, (80 mg, 0.319 mmol), 267.2 (M + H)⁺ 7.52(m, 3H), 8.03- 2%) 5-(4,4,5,5- (ES⁺), at 1.52 min, 8.09 (m, 3H), 8.31(d, tetramethyl-1,3,2- 96.4% purity J 2.6 Hz, 1H), 8.57 dioxaborolan-2-(method B). (d, J 7.5 Hz, 1H). yl)pyrazin-2-ol (159 mg, 0.717 mmol),Alternative Procedure for the Preparation of5,6-Biaryl-3-amino-1,2,4-triazines

The Suzuki reaction to form 5,6-biaryl-3-amino-1,2,4-triazines mayalternatively be performed with palladium-containing catalysts such asdichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II)or dichloro[1,1′-bis(di-tert-butylphosphino)]fenocene palladium(II).Residual palladium species may then be removed from a solution of thetriazine by treatment with a suitable scavenging agent, such asmercaptopropyl-functionalised silica (Quadrasil-MP; available fromJohnson Matthey) or macroporous polystyrene-bound2,4,6-trimercaptotriazine (MP-TMT; available from Biotage).

Typical Alternative to the General Procedure, as Exemplified withExample (xcv):

6-bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (1 molar eq.),2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-methylpyridine(1 molar eq.) and K₂CO₃ (1.5 molar eq.) are suspended in a mixture of1,4-dioxane and water (2:1; 10 mL of solvent per gram of bromotriazine).The resulting mixture is degassed, treated withdichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II)(2 mol %) and refluxed until full consumption of bromotriazine isobserved by LCMS. The cooled reaction mixture is then diluted withwater, extracted with DCM and passed through a phase separator. Theorganic phase is concentrated under reduced pressure and purified bygradient flash chromatography, eluting with mixtures of ethyl acetateand hexanes to afford6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine(61%).

Typical Alternative to General Procedure, as Exemplified with Example1(ccix):

6-bromo-5-phenyl-1,2,4-triazin-3-amine (1 molar eq.),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine(1 molar eq.) and K₂CO₃ (1.5 molar eq.) are suspended in a mixture of1,4-dioxane and water (2:1; 10 mL of solvent per gram of bromotriazine).The resulting mixture is degassed, treated withdichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II)(2 mol %) and refluxed until full consumption of bromotriazine isobserved by LCMS. The cooled reaction mixture is then diluted withwater, extracted with DCM and passed through a phase separator. Theorganic phase is concentrated under reduced pressure and purified bygradient flash chromatography, eluting with mixtures of ethyl acetateand hexanes to afford6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine(90%).

General Procedure for the Removal of Palladium Contaminants from5,6-Biaryl-3-amino-1,2,4-triazines

A solution of a 5,6-biaryl-3-amino-1,2,4-triazine derivative (100 mg) inDCM (1.5 mL) is treated with Quadrasil-MP (42 mg) or MP-TMT (35 mg). Theresulting mixture is heated to 50° C. for up to 24 hours then filtered.The filtrate is then concentrated under reduced pressure and theprocedure repeated, if necessary.

Quadrasil-MP is available from Johnson Matthey, MP-TMT is available fromBiotage.

Example 2

General procedure for the Preparation of5-Aryl-3,6-diamino-1,2,4-triazines

Intermediate D, a 6-halo-5-aryl-1,2,4-triazin-3-amine derivative (0.80mmol) is dissolved in dioxane or N-methyl-2-pyrolidone (5 mL) andtreated with an amine (1.60 mmol) and an aqueous solution of K₂CO₃ (0.22g, 1.60 mmol in 0.5 mL water). The mixture is heated in a microwave fortwo hrs at 140° C. with TLC monitoring (hexane/ethyl acetate, 1:1).After completion of the reaction the mixture is poured into water (50mL) and extracted with ethyl acetate (2×100 mL). The organic layers arecombined, dried over Na₂SO₄ and concentrated in vacuo. The crudecompound, product B, is purified by gradient flash chromatography orpreparative HPLC.

(i) 5-Phenyl-6-(piperidin-1-yl)-1,2,4-triazin-3-amine

5-Phenyl-6-(piperidin-1-yl)-1,2,4-triazin-3-amine (18 mg, 18%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol)and piperidine (0.14 g, 1.60 mmol) according to the general procedure ofExample 2.

HPLC purity: 96.95% (264 nm)

Mass spectroscopy: (ESI+ve) 256.0 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 1.56-1.62 (m, 6H), 3.03 (m, 4H), 4.89 (s,2H), 7.44-7.55 (m, 3H), 8.12 (m, 2H).

(ii) 6-(Morpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(Morpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (50 mg, 20%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol)and morpholine (0.126 g, 1.44 mmol) according to the general procedureof Example 2.

HPLC purity: 94.87% (265 nm)

Mass spectroscopy: (ESI+ve) 257.9 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 2.88 (t, 4H), 3.59 (t, 4H), 6.75 (s, 2H),7.54 (m, 3H), 8.06 (m, 2H).

(iii) 6-(3-Methylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Methylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (30 mg, 14%)was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80mmol) and 3-methylpiperidine (0.21 g, 1.92 mmol) according to thegeneral procedure of Example 2.

HPLC purity: 98.87% (215 nm)

Mass spectroscopy: (ESI+ve) 270.0 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 0.75 (d, 3H), 0.97 (m, 1H), 1.45 (m, 2H),1.65 (m, 2H), 2.20 (m, 2H), 3.14 (m, 2H), 6.65 (s, 2H), 7.49 (m, 3H),8.04 (m, 2H).

(iv) 6-(2,6-Dimethylmorpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(2,6-Dimethylmorpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (35 mg,10%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g,1.19 mmol) and 2,6-dimethylmorpholine (0.27 g, 2.39 mmol) according tothe general procedure of Example 2.

HPLC purity: 90% (271 nm)

Mass spectroscopy: (ESI+ve) 286.0 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 1.10 (s, 6H), 2.52 (t, 2H), 3.23 (d, 2H),3.71 (m, 2H), 5.06 (b, 2H), 8.07 (m, 3H), 8.07 (d, 2H).

(v) 6-(4,4-Difluoropiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(4,4-Difluoropiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (39 mg,14%) was prepared from 6-chloro-5-phenyl-1,2,4-triazin-3-amine (0.20 g,0.96 mmol), K₂CO₃ (0.23 g, 1.67 mmol) and 4,4-difluoropiperidinehydrochloride (0.22 g, 1.45 mmol) according to the general procedure ofExample 2.

HPLC purity: 98.48% (262 nm)

Mass spectroscopy: (ESI+ve) 292.0 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 1.97 (m, 4H), 3.04 (m, 4H), 6.76 (s, 2H),7.51 (m, 3H), 8.06 (m, 2H).

(vi) 6-(3,3-Dimethylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(3,3-Dimethylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (54 mg,10%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g,1.99 mmol) and 3,3-dimethylpiperidine (0.27 g, 2.39 mmol) according tothe general procedure of Example 2.

HPLC purity: 88% (274 nm)

Mass spectroscopy: (ESI+ve) 284.1 [M+H]⁺

¹H NMR: (400 MHz. DMSO) δ: 0.89 (s, 6H), 1.24 (m, 2H), 1.40 (m, 2H),2.65 (m, 2H), 2.70 (m, 2H), 6.67 (s, 2H), 7.49 (m, 3H), 7.94 (m, 2H).

(vii)5-Phenyl-6-[3-(trifluoromethyl)piperidin-1-yl]-1,2,4-triazin-3-amine

5-Phenyl-6-[3-(trifluoromethyl)piperidin-1-yl]-1,2,4-triazin-3-amine (50mg, 8%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50g, 1.99 mmol) and 3-(trifluoromethyl)piperidine (0.40 g, 2.58 mmol)according to the general procedure of Example 2.

HPLC purity: 97.6% (263 nm)

Mass spectroscopy: (ESI+ve) 324.1 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 1.35 (m, 1H), 1.48 (m, 1H), 1.57 (m, 1H),1.90 (m, 1H), 2.48 (m, 2H), 2.73 (m, 1H), 3.05 (m, 1H), 3.50 (m, 1H),6.74 (s, 2H), 7.50 (s, 3H), 8.02 (m, 2H).

(viii) 6-(Octahydroquinolin-1(2H)-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(Octahydroquinolin-1(2H)-yl)-5-phenyl-1,2,4-triazin-3-amine (39 mg,7%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (1.00 g,3.96 mmol) and decahydroquinoline (0.60 g, 4.36 mmol) according to thegeneral procedure of Example 2.

HPLC purity: 98.75% (282 nm)

Mass spectroscopy: (ESI+ve) 310.1 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 0.83 (m, 1H), 1.41 (m, 6H), 1.54 (m, 6H),2.62 (m, 1H), 2.80 (m, 2H), 6.93 (bs, 2H), 7.47 (m, 3H), 8.15 (m, 2H).

(ix) 6-(3-Methoxypiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Methoxypiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (33 mg, 4%)was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.70 g, 2.78mmol), K₂CO₃ (0.80 g, 5.85 mmol) and 3-methoxy piperidine HCl (0.52 g,3.34 mmol) according to the general procedure of Example 2.

HPLC purity: 99.32% (266 nm)

Mass spectroscopy: (ESI+ve) 286.0 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 1.36 (m, 1H), 1.45 (m, 1H), 1.59 (m, 1H),1.84 (m, 1H), 2.48 (m, 1H), 2.60 (m, 1H), 3.03 (m, 4H), 3.25 (m, 2H),7.57 (m, 3H), 7.26 (bs, 2H), 7.99 (m, 2H).

(x) 6-(3-Ethynylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Ethynylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (10 mg, 2%)was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.60 g, 2.40mmol) and 3-ethynyl piperidine HCl (0.42 g, 2.87 mmol) according to thegeneral procedure of Example 2.

HPLC purity: 95.99% (266 nm)

Mass spectroscopy: (ESI+ve) 280.0 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 1.08-1.80 (m, 5H), 2.64 (m, 2H), 2.86 (m,2H), 3.23 (t, 1H), 6.7 (bs, 2H), 7.48 (m, 3H), 8.06 (d, 2H).

(xi)6-(2,6-Dimethylmorpholin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine

6-(2,6-Dimethylmorpholin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine(110 mg, 20%) was prepared from6-bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (0.50 g, 1.87 mmol) and2,6-dimethylmorpholine (1.06 g, 9.36 mmol) according to the generalprocedure of Example 2.

HPLC purity: 93.61% (264 nm)

Mass spectroscopy: (ESI+ve) 304 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 1.12 (d, 6H), 2.54 (m, 2H), 3.19 (d, 2H),3.30 (m, 2H), 5.13 (bs, 2H), 7.16 (m, 2H), 8.16 (m, 2H).

The following compounds were prepared by reacting the indicated startingmaterials with potassium carbonate (83 mg, 0.60 mmol) in 1,4-dioxane(0.8 mL) and water (0.2 mL) at 140° C. for 18 hours, unless a shortertime is specified:

No. Product (yield) Prepared From LCMS NMR (xii) 6-(2- 6-bromo-5-phenyl-Mass (400 MHz, DMSO) δ: ethylmorpholino)-5- 1,2,4-triazin-3-aminespectroscopy: m/z 0.73 (t, J 7.5, 3H), phenyl-1,2,4-triazin- (150 mg,0.597 286 (M + H)⁺ (ES⁺), 1.22-1.44 (m, 2H), 3-amine (60 mg, mmol), 2-at 4.03 min, 100% 2.38-2.47 (m, 1H), 35%) ethylmorpholine (344 (methodB). 2.65-2.77 (m, 1H), mg, 2.99 mmol) 3.02 (d, J 12.2, 1H), 3.12 (d, J12.2, 1H), 3.33 (s, 1H), 3.48- 3.58 (m, 1H), 3.77 (d, J 11.1, 1H), 6.74(s, 2H), 7.48-7.57 (m, 3H), 8.01-8.08 (m, 2H). (xiii)5-phenyl-6-(6-oxa-9- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:azaspiro[4.5]decan- 1,2,4-triazin-3-amine spectroscopy: m/z 1.27-1.44(m, 2H), 9-yl)-1,2,4-triazin-3- (150 mg, 0.597 312 (M + H)⁺ (ES⁺),1.47-1.76 (m, 6H), amine (48 mg, 25%) mmol), 6-oxa-9- at 4.24 min, 97%2.71-2.81 (m, 2H), azaspiro[4.5]decane purity (method B). 2.84 (s, 2H),3.47- hydrochloride (425 3.63 (m, 2H), 6.77 (s, mg, 2.390 mmol) 2H),7.48-7.57 (m, 3H), 7.94-8.01 (m, 2H). (xiv) 6-(2,2- 6-bromo-5-phenyl-Mass (400 MHz, DMSO) δ: diethylmorpholino)-5- 1,2,4-triazin-3-aminespectroscopy: m/z 0.67 (t, J 7.5, 6H), phenyl-1,2,4-triazin- (150 mg,0.597 314 (M + H)⁺ (ES⁺), 1.33 (dq, J 14.8, 7.5, 3-amine (47 mg, mmol),2.2- at 4.64 min, 100% 2H), 1.65 (dq, J 14.9, 25%) diethylmorpholine(method B). 7.5, 2H), 2.71-2.82 (428 mg, 2.99 mmol) (m, 4H), 3.47-3.58(m, 2H), 6.78 (s, 2H), 7.45-7.57 (m, 3H), 7.85-7.95 (m, 2H). (xv)6-(2,2- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: dimethylmorpholino)-1,2,4-triazin-3-amine spectroscopy: m/z 1.14 (s, 6H), 2.69-5-phenyl-1,2,4- (150 mg, 0.597 286 (M + H)⁺ (ES⁺), 2.77 (m, 2H), 2.79(s, triazin-3-amine (41 mmol), 2,2- at 4.03 min, 98% 2H), 3.49-3.62 (m,mg, 24%); prepared dimethylmorpholine (method B). 2H), 6.77 (s, 2H), in6 hours (344 mg, 2.99 mmol) 7.48-7.56 (m, 3H), 7.92-8.00 (m, 2H). (xvi)(1-(3-amino-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:phenyl-1,2,4-triazin- 1,2,4-triazin-3-amine spectroscopy: m/z 0.88 (s,3H), 1.10- 6-yl)-3- (150 mg, 0.597 300 (M + H)⁺ (ES⁺), 1.20 (m, 1H),1.31- methylpiperidin-3- mmol), (3- at 4.10 min, 99% 1.45 (m, 3H), 2.54-yl)methanol (35 mg, methylpiperidin-3- (method B). 2.63 (m, 1H), 2.63-19%); prepared in 6 yl)methanol (386 mg, 2.72 (m, 1H), 2.75- hours 2.99mmol) 2.93 (m, 2H), 3.23 (d, J 5.6, 2H), 4.51 (t, J 5.5, 1H), 6.68 (s,2H), 7.47-7.55 (m, 3H), 7.92-8.00 (m, 2H). (xvii) 6-(3-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (methoxymethyl)piper-1,2,4-triazin-3-amine spectroscopy: m/z 0.95-1.12 (m, 1H),idin-1-yl)-5-phenyl- (150 mg, 0.597 300 (M + H)⁺ (ES⁺), 1.37-1.60 (m,2H), 1,2,4-triazin-3-amine mmol), cis-3- at 4.4 min, 100% 1.61-1.73 (m,1H), (75 mg, 42%) (methoxymethyl)piper- (method B). 1.80-1.94 (m, 1H),idine (386 mg, 2.99 2.37-2.47 (m, 1H), mmol) 2.50-2.58 (m, 1H),3.03-3.21 (m, 6H), 3.28-3.34 (m, 1H), 6.68 (s, 2H), 7.47- 7.56 (m, 3H),7.99- 8.09 (m, 2H). (xviii) 1-(1-(3-amino-5- 6-bromo-5-phenyl- Mass (400MHz, DMSO) δ: phenyl-1,2,4-triazin- 1,2,4-triazin-3-amine spectroscopy:m/z 0.91-1.03 (m, 1H), 6-yl)piperidin-3- (150 mg, 0.597 m/z 300 (M + H)⁺1.22-1.32 (m, 2H), yl)ethanol (80 mg, mmol) and 1- (ES⁺), at 3.98 min,1.38-1.59 (m, 2H), 43%) (piperidin-3- 96% (method B). 1.59-1.69 (m, 1H),yl)ethanol (77 mg, 1.69-1.80 (m, 1H), 0.597 mmol) 2.28-2.38 (m, 1H),2.47-2.56 (m, 1H), 3.07-3.16 (m, 1H), 3.18-3.30 (m, 3H), 4.25-4.38 (m,1H), 6.68 (s, 2H), 7.46- 7.57 (m, 3H), 7.99- 8.09 (m, 2H). (xix)(1-(3-amino-5- piperidin-3- Mass (400 MHz, DMSO) δ:phenyl-1,2,4-triazin- ylmethanol (344 mg, spectroscopy: m/z 0.94-1.08(m, 1H), 6-yl)piperidin-3- 2.99 mmol) 6-bromo- 286 (M + H)⁺ (ES⁺),1.34-1.57 (m, 2H), yl)methanol (18 mg, 5-phenyl-1,2,4- at 3.78 min, 94%1.61-1.74 (m, 2H), 10%) triazin-3-amine (150 (method B). 2.38-2.61 (m,2H), mg, 0.597 mmol) 3.04 (s, 1H), 3.13- 3.46 (m, 3H), 4.44 (t, J = 5.3Hz, 1H), 6.67 (s, 2H), 7.45-7.57 (m, 3H), 7.98-8.11 (m, 2H). (xx)1-(1-(3-amino-5- 1-(piperidin-3- Mass (400 MHz, DMSO) δ:phenyl-1,2,4-triazin- yl)ethanone (380 mg, spectroscopy: m/z 1.30-1.51(m, 2H), 6-yl)piperidin-3- 2.99 mmol), 6- 298 (M + H)⁺ (ES⁺); 1.52-1.63(m, 1H), yl)ethanone (13 mg, bromo-5-phenyl- at 3.92 min, 1.85-1.96 (m,1H), 7%) 1,2,4-triazin-3-amine 95.06% (method 2.01 (s, 3H), 2.62- (150mg, 0.597 B). 2.71 (m, 1H), 2.71- mmol) 2.83 (m, 1H), 2.95- 3.12 (m,1H), 3.31- 3.46 (m, 2H), 6.72 (s, 2H), 7.46-7.56 (m, 3H), 7.97-8.08 (m,3H). (xxi) 6- 6-bromo-5-phenyl- HPLC purity: (400 MHz, DMSO) δ:(octahydroisoquinolin- 1,2,4-triazin-3-amine 97.40% (277 nm); 0.85 (m,3H), 1.14 2(1H)-yl)-5-phenyl- (2.00 g, 7.96 mmol) mass (m, 4H), 1.36 (m,2H), 1,2,4-triazin-3-amine and per spectroscopy: 1.54 (m, 3H), 2.26(54.2 mg, 2.1%); hydroisoquinoline (ESI +ve) m/z (m, 1H), 2.51 (m, 1H),prepared in 8 hours (2.21 g, 15.9 mmol) 310.1 [M + H]⁺ 3.10 (m, 2H),6.61 (bs, 2H), 7.48 (m, 3H), 8.04 (dd, 2H). (xxii) N⁶-(4-methyl-1,3-6-bromo-5-phenyl- HPLC purity: (400 MHz, DMSO) δ: thiazol-2-yl)-5-1,2,4-triazin-3-amine 99.03% (298 nm); 2.10 (s, 3H), 6.18 (s,phenyl-1,2,4-triazine- (1.00 g, 3.98 mmol) mass 1H), 6.53 (bs, 2H),3,6-diamine (10 mg, and 2-amino-4- spectroscopy: 7.48 (m, 3H), 8.15 1%)methyl thiazole (1.36 (ESI +ve) m/z (m, 2H), 11.61 (b, g, 11.95 mmol)284.9 [M + H]⁺ 1H). (xxiii) 5-phenyl-6-[4- 6-bromo-5-phenyl- HPLCpurity: (400 MHz, DMSO) δ: (trifluoromethyl)piperidin-1,2,4-triazin-3-amine 99.9% (218 nm); 1.46 (m, 2H), 1.751-yl]-1,2,4-triazin- (1.0 g, 3.9 mmol) and mass (m, 2H), 2.34 (m, 1H)3-amine (20 mg, 2%) 4-trifluoromethyl spectroscopy: 2.66 (m, 2H), 3.23piperidine (ESI +ve) m/z (m, 2H), 6.72 (s, 2H), hydrochloride (0.9 g,323.9 [M]⁺ 7.51 (m, 3H), 8.02 4.8 mmol) (m, 2H). (xxiv) 5-phenyl-6-(3-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: phenylpiperidin-1-yl)-1,2,4-triazin-3-amine spectroscopy: m/z 1.51-1.77 (m, 3H),1,2,4-triazin-3-amine (150 mg, 0.597 332 (M + H)⁺ (ES⁺), 1.83-1.92 (m,1H), (62 mg, 31%) mmol), 3- at 4.92 min, 100% 2.58-2.72 (m, 2H),phenylpiperidine (method B). 2.74-2.84 (m, 1H), (482 mg, 2.99 mmol) 3.24(d, J 11.7, 1H) 3.34 (d, J 11.7, 1H), 6.67 (s, 2H), 7.04- 7.12 (m, 2H),7.13- 7.20 (m, 1H), 7.20- 7.28 (m, 2H), 7.52- 7.58 (m, 3H), 8.03- 8.13(m, 2H). (xxv) (4-(3-amino-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:phenyl-1,2,4-triazin- 1,2,4-triazin-3-amine spectroscopy: 2.51-2.58 (m,1H), 6-yl)morpholin-2- (150 mg, 0.597 m/z 288 (M + H)⁺ 2.63-2.74 (m,1H), yl)methanol (40 mg, mmol), morpholin-2- (ES⁺), at 2.95 min,2.91-3.02 (m, 1H), 23%) ylmethanol (350 mg, 100% (method B). 3.33 (s,3H), 3.47- 2.99 mmol) 3.58 (m, 2H), 3.70- 3.79 (m, 1H), 4.67 (t, J 5.8,1H), 6.76 (s, 2H), 7.47-7.56 (m, 3H), 8.03-8.11 (m, 2H). (xxvi)5-phenyl-6-(3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:(propoxymethyl)pyrrolidin- 1,2,4-triazin-3-amine spectroscopy: 0.80 (t,J 7.4, 3H), 1-yl)-1,2,4- (150 mg, 0.597 m/z 314 (M + H)⁺ 1.37-1.58 (m,3H), triazin-3-amine (39 mmol), 3- (ES⁺), at 4.64 min, 1.81-1.94 (m,1H), mg, 20%) (propoxymethyl)pyrrolidine 95% (method B). 2.29-2.40 (m,2H), (428 mg, 2.99 2.85 (dd, J 10.3, 6.4, mmol) 1H), 3.00-3.13 (m, 3H),3.18-3.30 (m, 3H), 6.38 (s, 2H), 7.45-7.53 (m, 3H), 7.69-7.79 (m, 2H).(xxvii) 2-(1-(3-amino-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:phenyl-1,2,4-triazin- 1,2,4-triazin-3-amine spectroscopy: 0.86 (s, 6H),1.00- 6-yl)piperidin-3- (150 mg, 0.597 m/z 314 (M + H)⁺ 1.13 (m, 1H),1.38- yl)propan-2-ol (56 mmol), 2-(piperidin- (ES⁺), 4.22 min, 1.52 (m,2H), 1.58- mg, 31%) 3-yl)propan-2-ol (257 100% (method B). 1.69 (m, 1H),1.78- mg, 1.792 mmol) 1.88 (m, 1H), 2.30 (app t, J 11.6, 1H), 2.42-2.50(m, 1H), 3.20-3.28 (m, 1H), 3.31-3.38 (m, 1H), 4.07 (s, 1H), 6.65 (s,2H), 7.45-7.56 (m, 3H), 7.97-8.09 (m, 2H), (xxviii) 6- 6-bromo-5-phenyl-Mass (400 MHz, DMSO) δ: (hexahydropyrrolo[1,2- 1,2,4-triazin-3-aminespectroscopy: 1.21-1.35 (m, 2H), a]pyrazin-2(1H)-yl)- (150 mg, 0.597 m/z297 (M + H)⁺ 1.55-1.73 (m, 2H), 5-phenyl-1,2,4- mmol), (ES⁺), at 4.17min, 1.96-2.20 (m, 3H), triazin-3-amine (16 octahydropyrrolo[1,2- 100%(method B). 2.69-2.81 (m, 1H), mg, 9%) a]pyrazine (377 mg, 2.81-3.03 (m,2H), 2.99 mmol) 3.06-3.19 (m, 1H), 3.29-3.36 (m, 2H), 6.71 (s, 2H),7.46- 7.56 (m, 3H), 8.00- 8.09 (m, 2H). (xxix) 1-(3-amino-5-phenyl-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)-3-1,2,4-triazin-3-amine spectroscopy: 0.79 (t, J 7.4, 3H),ethylpiperidin-3-ol (150 mg, 0.597 m/z 300 (M + H)⁺ 1.23 (s, 1H), 1.32-(42 mg, 23%) mmol), 3- (ES⁺), at 4.14 min, 1.52 (m, 4H), 1.54-ethylpiperidin-3-ol 97% (method B). 1.68 (m, 1H), 2.59- (386 mg, 2.99mmol) 2.69 (m, 1H), 2.69- 2.80 (m, 1H), 2.86- 2.98 (m, 2H), 4.21 (s,1H), 6.73 (s, 2H), 7.46-7.55 (m, 3H), 8.01-8.10 (m, 2H). (xxx)2-(4-(3-amino-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:phenyl-1,2,4-triazin- 1,2,4-triazin-3-amine spectroscopy: 1.34-1.61 (m,2H), 6-yl)morpholin-2- (150 mg, 0.597 m/z 302 (M + H)⁺ 2.48-2.58 (m,1H), yl)ethanol (42 mg, mmol), 2-(morpholin- (ES⁺), at 3.22 min,2.62-2.74 (m, 1H), 22%); prepared in 3 2-yl)ethanol (392 mg, 96% (methodB). 2.91-3.02 (m, 1H), hours 2.99 mmol) 3.09-3.20 (m, 1H), 3.27-3.42 (m,2H), 3.46-3.56 (m, 1H), 3.56-3.67 (m, 1H), 3.68-3.78 (m, 1H), 4.39 (t, J5.1, 1H), 6.74 (s, 2H), 7.47- 7.58 (m, 3H), 7.99- 8.12 (m, 2H).

Example 3

General Procedure for the Preparation of3-amino-5-aryl-1-aryloxy-1,2,4-triazines

A solution of intermediate D, a 6-halo-5-aryl-1,2,4-triazin-3-amine,(1.99 mmol) in DMSO (5 mL) is treated sequentially with a phenolderivative (7.90 mmol), NaOH (0.31 g, 7.9 mmol) and cesium carbonate(0.64 g, 1.99 mmol). The resulting mixture is stirred at 90° C.overnight with TLC monitoring (hexane/ethyl acetate, 7:3). Uponcompletion of the reaction, the mixture is diluted with water (15 mL)and extracted with ethyl acetate (3×15 mL). The combined organicextracts are dried over sodium sulfate and concentrated in vacuo. Thecrude product, product C, is purified by gradient flash chromatography,eluting with mixtures of ethyl acetate in hexane (e.g. 15%) or bypreparative HPLC.

(i) 6-Phenoxy-5-phenyl-1,2,4-triazin-3-amine

6-Phenoxy-5-phenyl-1,2,4-triazin-3-amine (78 mg, 14%) was prepared from6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.5 g, 1.99 mmol) and phenol(0.74 g, 7.90 mmol) according to the general procedure of Example 3.

HPLC purity: 99.67% (210 nm)

Mass spectroscopy: (ESI+ve) 265.0 [M+H]⁺.

¹H NMR: (400 MHz, CDCl₃) δ: 7.08 (s, 2H), 7.13 (m, 3H), 7.36 (m, 2H),7.52 (m, 3H), 8.07 (m, 2H).

(ii) 6-(3-Aminophenoxy)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Aminophenoxy)-5-phenyl-1,2,4-triazin-3-amine (25 mg, 8%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol)and 3-amino phenol (0.19 g, 1.78 mmol) according to the generalprocedure of Example 3.

HPLC purity: 89.7% (238 nm)

Mass spectroscopy: (ESI+ve) 338.0 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 5.19 (s, 2H), 6.15 (m, 2H), 6.27 (m, 1H),6.93 (m, 1H), 7.10 (s, 2H), 7.48-7.56 (m, 3H), 8.04 (d, 2H).

(iii) 6-(3-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (78 mg, 23%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol)and 3-fluoro phenol (0.27 g, 2.39 mmol) according to the generalprocedure of Example 3.

HPLC purity: 99.67% (244 nm)

Mass spectroscopy: (ESI+ve) 283.1 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 5.29 (s, 2H), 6.87-6.95 (m, 3H), 7.33 (m,1H), 7.48-7.58 (m, 3H), 8.23 (m, 2H).

(iv) 5-Phenyl-6-[2-(propan-2-yl)phenoxy]-1,2,4-triazin-3-amine

5-Phenyl-6-[2-(propan-2-yl)phenoxy]-1,2,4-triazin-3-amine (20 mg, 7%)was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59mmol) and 2-isopropyl phenol (0.43 g, 3.18 mmol) according to thegeneral procedure of Example 3.

HPLC purity: 96.5% (245 nm)

Mass spectroscopy: (ESI+ve) 307.1 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 1.25 (d, 6H), 3.16 (m, 1H), 5.19 (s, 2H),7.00 (m, 1H), 7.20 (m, 2H), 7.36 (m, 1H), 7.38-7.59 (m, 3H), 8.31 (m,2H).

(v) 5-Phenyl-6-[3-(trifluoromethyl)phenoxy]-1,2,4-triazin-3-amine

5-Phenyl-6-[3-(trifluoromethyl)phenoxy]-1,2,4-triazin-3-amine (21 mg,4%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g,1.59 mmol) and 3-(trifluoromethyl)phenol (0.52 g, 3.18 mmol) accordingto the general procedure of Example 3.

HPLC purity: 88.72% (245 nm)

Mass spectroscopy: (ESI+ve) 332.9 [M+H]⁺

¹H NMR: (400 MHz, de-DMSO) δ: 7.10 (s, 2H), 7.49-7.63 (m, 5H), 7.61-7.63(m, 2H), 8.07-8.09 (d, 2H).

(vi) 6-(4-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine

6-(4-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (35 mg, 8%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol)and 4-fluorophenol (0.36 g, 3.18 mmol) according to the generalprocedure of Example 3.

HPLC purity: 96.39% (244 nm)

Mass spectroscopy: (ESI+ve) 283.1 [M+H]⁺

¹H NMR: (400 MHz, de-DMSO) δ: 7.03 (s, 2H), 7.20-7.22 (m, 4H), 7.50-7.56(m, 3H), 8.08 (dd, 2H).

(vii) 6-(2-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine

6-(2-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (44 mg, 10%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol)and 2-fluorophenol (0.36 g, 3.18 mmol) according to the generalprocedure of Example 3.

HPLC purity: 90.06% (244 nm)

Mass spectroscopy: (ESI+ve) 283.1 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 7.04 (s, 2H), 7.25 (m, 2H), 7.37 (m, 2H),7.53-8.11 (m, 3H), 8.12 (m, 2H).

(viii) 6-(4-Methoxyphenoxy)-5-phenyl-1,2,4-triazin-3-amine

6-(4-Methoxyphenoxy)-5-phenyl-1,2,4-triazin-3-amine (45 mg, 13%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol)and 4-methoxyphenol (0.30 g, 2.39 mmol) according to the generalprocedure of Example 3.

HPLC purity: 92.08% (218 nm)

Mass spectroscopy: (ESI+ve) 295.1 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 3.81 (s, 3H), 5.29 (s, 2H), 6.92 (d, 2H),7.08 (d, 2H), 7.50-7.59 (m, 3H), 8.29 (m, 2H).

(ix)6-[4-Fluoro-3-(trifluoromethyl)phenoxy]-5-phenyl-1,2,4-triazin-3-amine

6-[4-Fluoro-3-(trifluoromethyl)phenoxy]-5-phenyl-1,2,4-triazin-3-amine(198 mg, 36%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine(0.40 g, 1.59 mmol) and 4-fluoro-3-(trifluoromethyl)phenol (0.57 g, 3.18mmol) according to the general procedure of Example 3.

HPLC purity: 95% (235 nm)

Mass spectroscopy: (ESI+ve) 350.9 [M+H]J, (ESI−ve) 349.1[M−H]⁻.

¹H NMR: (400 MHz, DMSO) δ: 7.05 (s, 2H), 7.50-7.62 (m, 5H), 7.75 (m,1H), 8.10 (m, 2H).

(x) 5-Phenyl-6-[3-(trifluoromethoxy)phenoxy]-1,2,4-triazin-3-amine

5-Phenyl-6-[3-(trifluoromethoxy)phenoxy]-1,2,4-triazin-3-amine (22 mg,3%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g,1.99 mmol) and 3-(trifluoromethoxy)phenol (0.42 g, 2.39 mmol) accordingto the general procedure of Example 3.

HPLC purity: 95.6% (235 nm)

Mass spectroscopy: (ESI+ve) 348.9 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 5.17 (s, 2H), 7.08 (m, 3H), 7.39 (t, 1H)7.54 (m, 3H), 8.21 (d, 2H).

(xi) 6-(3-Chlorophenoxy)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Chlorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (147 mg, 31%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.58 mmol)3-chloro phenol (0.40 g, 3.16 mmol) and K₂CO₃ (432 mg, 3.15 mmol),according to the general procedure of Example 3.

HPLC purity: 98% (245 nm)

Mass spectroscopy: (ESI+ve) 298.9 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 7.12 (s, 2H), 7.14 (m, 1H), 7.21 (m, 1H),7.35 (m, 1H), 7.40 (m, 1H), 7.55 (m, 3H), 8.06 (m, 2H).

(xii) 6-(3,5-Dichlorophenoxy)-5-phenyl-1,2,4-triazin-3-amine

6-(3,5-Dichlorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (89 mg, 17%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol)and 3-5-dichlorophenol (0.52 g, 3.18 mmol) according to the generalprocedure of Example 3.

HPLC purity: 99.03% (246 nm)

Mass spectroscopy: (ESI+ve) 332.9 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 7.15 (s, 2H), 7.40 (m, 3H), 7.54 (m, 3H),8.02 (d, 2H).

(xiii) 6-(3,5-Difluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine

6-(3,5-Difluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (101 mg, 17%) wasprepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol)and 3,5-difluorophenol (0.31 g, 3.98 mmol) according to the generalprocedure of Example 3.

HPLC purity: 90.33% (244 nm)

Mass spectroscopy: (ESI+ve) 300.9 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ: 5.46 (bs, 2H), 6.65 (m, 1H), 6.71 (m, 2H),7.50 (m, 2H), 7.58 (m, 1H), 8.12 (m, 2H).

The following compounds were prepared by reacting the indicated startingmaterials according to the general procedure of Example 3.

No. Product (yield) Prepared From LCMS NMR (xiv) 6-(3,5-6-bromo-5-phenyl- HPLC purity: (400 MHz, DMSO) δ: dimethylphenoxy)-5-1,2,4-triazin-3-amine 96.6% (246 nm); 2.22 (s, 6H), 6.71 (s,phenyl-1,2,4-triazin- (0.40 g, 1.59 mmol) mass 2H), 6.76 (s, 1H) 7.063-amine (26 mg, 5%) and 3,5-(dimethyl) spectroscopy: (s, 2H), 7.52 (m,3H), phenol (0.39 g, 2.07 (ESI +ve) m/z 8.05 (d, 2H). mmol) 293.0 [M +H]⁺ (xv) 6-(3-chloro-5- 6-bromo-5-phenyl- HPLC purity: 98% (400 MHz,DMSO) δ: methoxyphenoxy)-5- 1,2,4-triazin-3-amine (245 nm); mass 3.74(s, 3H), 6.75 (m, phenyl-1,2,4-triazin- (0.40 g, 1.59 mmol)spectroscopy: 1H), 6.82 (m, 1H), 3-amine (120 mg, and 3-chloro-5- (ESI+ve) m/z 6.85 (m, 1H), 7.12 (s, 23%) methoxyphenol (0.50 328.9 [M + H]⁺2H), 7.53 (m, 3H), g, 31.8 mmol) 8.03 (m, 2H).

The following compounds were prepared by heating the neat mixture of aphenol derivative and bromotriazine derivative (as indicated) with DBU(270 μl, 1.792 mmol), at 110° C. overnight:

No. Product (yield) Prepared From LCMS NMR (xvi) 1-(3-amino-5-phenyl-6-chloro-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-1,2,4-triazin-3-amine spectroscopy: m/z 6.08-6.16 (m, 2H),yl)pyridin-4(1H)-one (0.082 g, 0.393 266.2 (M + H)⁺ (ES⁺); 7.42-7.55 (m,5H), (29 mg, 0.109 mmol, mmol), DBU (0.298 264.4 (M − H)⁻ (ES⁻),7.68-7.77 (m, 4H). 27.5%) μl, 1.990 mmol) and at 2.45 min, 100%pyridin-4-ol (189 mg, (method B). 1.990 mmol) (xvii)6-(4-methylphenoxy)- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:5-phenyl-1,2,4- 1,2,4-triazin-3-amine spectroscopy: m/z 2.28 (s, 3H),7.00- triazin-3-amine (51 (90 mg, 0.358 279.82 (M + H)⁺ 7.04 (m, 2H),7.05 (s, mg, 51%) mmol), p-cresol (194 (ES⁺), at 4.75 min, 2H),7.12-7.22 (m, mg, 1.792 mmol), 99% (method B). 2H), 7.49-7.60 (m, andDBU (270 μl, 3H), 8.04-8.13 (m, 1.792 mmol) 2H). (xviii)6-(4-chlorophenoxy)- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:5-phenyl-1,2,4- 1,2,4-triazin-3-amine spectroscopy: m/z 7.12 (s, 2H),7.18- triazin-3-amine (38 (90 mg, 0.358 299.6 (M + H)⁺ (ES⁺), 7.25 (m,2H), 7.40- mg, 35%) mmol), 4- at 4.77 min, 99% 7.46 (m, 2H), 7.49-chlorophenol (230 (method B). 7.60 (m, 3H), 8.03- mg, 1.792 mmol), 8.11(m, 2H). and DBU (270 μl, 1.792 mmol) (xix) 6-(3,4- 6-bromo-5-phenyl-Mass (400 MHz, DMSO) δ: difluorophenoxy)-5- 1,2,4-triazin-3-aminespectroscopy: m/z 7.03-7.11 (m, 1H), phenyl-1,2,4-triazin- (90 mg, 0.358301.64 (M + H)⁺ 7.11 (s, 2H), 7.41- 3-amine mmol), 3,4- (ES⁺); 299.94 (M− 7.51 (m, 3H), 7.51- difluorophenol (233 H)⁻ (ES⁻), at 4.59 7.61 (m,3H), 8.03- mg, 1.792 mmol), min, 97% (method 8.11 (m, 2H). and DBU (270μl, B). 1.792 mmol) (xx) 6-[(6-methoxypyridin- 6-bromo-5-phenyl- Mass(400 MHz, DMSO) δ: 3-yl)oxy]-5-phenyl- 1,2,4-triazin-3-aminespectroscopy: m/z 3.85 (s, 3H), 6.88 1,2,4-triazin-3-amine (90 mg, 0.358296.0 (M + H)⁺ (ES⁺): (dd, J 8.9, 0.5, 1H), mmol), 6- 4.59 min, 95% 7.00(s, 2H), 7.52- methoxypyridin-3-ol (method B). 7.63 (m, 3H), 7.68 (224mg, 1.792 (dd, J 8.9, 3.0, 1H), mmol), and DBU 8.11 (dd, J 2.9, 0.5,(270 μl, 1.792 mmol) 1H), 8.12-8.16 (m, 2H). (xxi)6-[(2-methylpyridin-3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:yl)oxy]-5-phenyl- 1,2,4-triazin-3-amine spectroscopy: m/z 2.38 (s, 3H),7.05 (s, 1,2,4-triazin-3-amine (90 mg, 0.358 280.73 (M + H)⁺ 2H), 7.28(ddd, J 8.2, mmol), 2- (ES⁺); 278.94 (M − 4.7, 0.5, 1H), 7.52-methylpyridin-3-ol H)⁻ (ES⁻), at 3.90 7.63 (m, 4H), 8.11- (196 mg, 1.792min, 99% (method 8.18 (m, 2H), 8.31 mmol), and DBU B). (dd, J 4.7, 1.4,1H). (270 μl 1.792 mmol) (xxii) 6-[(6-chloropyridin-3- 6-bromo-5-phenyl-Mass (400 MHz, DMSO) δ: yl)oxy]-5-phenyl- 1,2,4-triazin-3-aminespectroscopy: m/z 7.14 (s, 2H), 7.51- 1,2,4-triazin-3-amine (90 mg,0.358 300.70 (M + H)⁺ 7.63 (m, 4H), 7.83 mmol), 6- (ES⁺), at 3.90 min,(dd, J 8.7, 3.0, 1H), chloropyridin-3-ol 97% (method B). 8.06-8.13 (m,2H), (232 mg, 1.792 8.42 (dd, J 3.0, 0.5, mmol), and DBU 1H). (270 μl,1.792 mmol) (xxiii) 4-[(3-amino- 6-bromo-5-phenyl- Mass (400 MHz, DMSO)δ: 5-phenyl-1,2,4- 1,2,4-triazin-3-amine spectroscopy: m/z 7.28 (s, 2H),7.34- triazin-6- (90 mg, 0.358 290.72 (M + H)⁺ 7.39 (m, 2H), 7.48-yl)oxy]benzonitrile mmol), 4- (ES⁺); 288.96 (M − 7.59 (m, 3H), 7.82-hydroxybenzonitrile H)⁻ (ES⁻), at 4.09 7.90 (m, 2H), 8.00- (213 mg,1.792 min, 99% (method 8.05 (m, 2H). mmol), and DBU B). (270 μl, 1.792mmol) (xxiv) 6-{[1-methyl-3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ:(trifluoromethyl)-1H- 1,2,4-triazin-3-amine spectroscopy: m/z 3.79 (s,3H), 6.58 (s, pyrazol-5-yl]oxy}-5- (90 mg, 0.358 337.60 (M + H)⁺ 1H),7.27 (s, 2H), phenyl-1,2,4-triazin- mmol), 1-methyl-3- (ES⁺); 335.81 (M− 7.52-7.66 (m, 3H), 3-amine (trifluoromethyl)-1H- H)⁻ (ES⁻), at 4.358.04-8.12 (m, 2H). pyrazol-5-ol (298 min, 97% (method mg, 1.792 mmol),B). and DBU (270 μl, 1.792 mmol) (xxv) 6-[(1-methyl-1H-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: benzimidazol-5-1,2,4-triazin-3-amine spectroscopy: m/z 3.85 (s, 3H), 7.01 (s,yl)oxy]-5-phenyl- (90 mg, 0.358 319.69 (M + H)⁺ 2H), 7.14 (dd, J 8.7,1,2,4-triazin-3-amine mmol), 1-methyl-1H- (ES⁺), at 4.05 min, 2.2, 1H),7.42 (d, J benzo[d]imidazol-5- 99% (method B). 2.1, 1H), 7.51-7.63 ol(266 mg, 1.792 (m, 4H), 8.12-8.19 mmol) and DBU (270 (m, 2H), 8.26 (s,1H). μl, 1.792 mmol) (xxvi) 1-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass(400 MHz, DMSO) δ: 1,2,4-triazin-6- 1,2,4-triazin-3-amine spectroscopy:m/z 6.54 (dd, J 8.0, 3.1, yl)pyridazin-4(1H)- (90 mg, 0.358 267.80⁺(ES⁺); 1H), 7.41-7.56 (m, one mmol), pyridazin-4-ol 266.01 (M − H)⁻(ES⁻), 5H), 7.74 (dd, J 3.1, (172 mg, 1.792 at 2.80 min, 96% 0.6, 1H),7.90 (s, 2H), mmol), and DBU (method B). 8.60 (dd, J 8.0, 0.6, (270 μl,1.792 mmol) 1H). (xxvii) 1-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass(400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)- 1,2,4-triazin-3-aminespectroscopy: m/z 7.44-7.60 (m, 5H), 3,5-dichloropyridin- (150 mg, 0.597334.55 (M + H)⁺ 7.94 (s, 2H), 8.42 (s, 4(1H)-one (10 mg, mmol), 3,5-(ES⁺), at 3.05 min, 2H). 5%) dichloropyridin-4-ol 96% (method B). (490mg, 2.99 mmol), (xxviii) 6-(2,4- 6-bromo-5-phenyl- Mass (400 MHz, DMSO)δ: dichlorophenoxy)-5- 1,2,4-triazin-3-amine spectroscopy: 7.10 (s, 2H),7.42- phenyl-1,2,4-triazin- (90 mg, 0.358 m/z 333.5 (M + H)+ 7.51 (m,2H), 7.54- 3-amine (16 mg, mmol), 2,4- (ES+), at 5.03 min, 7.64 (m, 3H),7.80 (d, 13%) dichlorophenol (292 98% purity (method J 2.4, 1H), 8.11-mg, 1.792 mmol), B). 8.18 (m, 2H). and DBU (270 μl, 1.792 mmol) (xxix)6-(2,4- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: difluorophenoxy)-5-1,2,4-triazin-3-amine spectroscopy: m/z 7.06 (s, 2H), 7.12-phenyl-1,2,4-triazin- (90 mg, 0.358 301.67 (M + H)⁺ 7.21 (m, 1H), 7.44-3-amine (12 mg, mmol), 2,4- (ES⁺), 99% (method 7.65 (m, 5H), 8.09- 11%)difluorophenol (233 B). 8.18 (m, 2H). mg, 1.792 mmol) and DBU (270 μl,1.792 mmol) (xxx) 5-phenyl-6-(pyridin- 6-bromo-5-phenyl- Mass (400 MHz,DMSO) δ: 3-yloxy)-1,2,4-triazin- 1,2,4-triazin-3-amine spectroscopy: m/z7.11 (s, 2H), 7.45 3-amine (90 mg, 0.358 266.76 (M + H)⁺ (ddd, J 8.4,4.7, 0.6, mmol), pyridin-3-ol (ES⁺); 264.96 (M − 1H), 7.50-7.63 (m, (170mg, 1.792 H)⁻ (ES⁻), at 3.70 3H), 7.69 (ddd, J 8.4, mmol) min, 99%(method 2.8, 1.4, 1H), 8.05- B). 8.15 (m, 2H), 8.41 (dd, J 4.7, 1.3,1H), 8.53 (d, J 2.5, 1H). (xxxi) 6-[(4-methylpyridin-3-6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: yl)oxy]-5-phenyl-1,2,4-triazin-3-amine spectroscopy: m/z 2.19 (s, 3H), 7.02 (s,1,2,4-triazin-3-amine (90 mg, 0.358 280.79 (M + H)⁺ 2H), 7.39 (d, J 4.9,mmol), 4- (ES⁺), at 3.97 min, 1H), 7.54-7.64 (m, methylpyridin-3-ol 99%(method B). 3H), 8.13-8.21 (m, (196 mg, 1.792 2H), 8.32 (d, J 4.8, mmol)1H), 8.39 (s, 1H). (xxxii) 5-phenyl-6-(p- 6-bromo-5-phenyl- Mass (400MHz, DMSO) δ: tolylthio)-1,2,4- 1,2,4-triazin-3-amine spectroscopy: m/z2.26 (s, 3H), 7.09- triazin-3-amine (407 (0.50 g, 1.991 mmol) 295.2 (M +H)⁺ (ES⁺), 7.15 (m, 4H), 7.44 (s, mg, 1.383 mmol, and 4- at 4.77 min,100% 2H), 7.46-7.55 (m, 69.4%) methylbenzenethiol (method B). 3H),7.67-7.72 (m, (1.24 g, 9.96 mmol) 2H).

Example 4 Preparation of (i)3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenol; and (ii)3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyltrifluoro-methanesulfonateStep 1: 3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenol

3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenol (890 mg, 85%) wasprepared by demethylation of6-(3-chloro-5-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (1.2 g, 3.84mmol; vide supra) with BBr₃ (5 mL) at −70° C. for 2 hours and then for afurther 16 hours at RT. The resulting mixture was then poured into water(25 mL) and extracted with DCM (3×30 mL). The combined organic extractswere then dried over Na₂SO₄ and concentrated under vacuum. The crudecompound was purified by gradient flash chromatography, eluting with 30%ethyl acetate in hexane to afford the target compound.

HPLC purity: 96.94% (262 nm)

Mass spectroscopy: (ESI+ve) 298.9 [M+H]⁺.

¹H NMR: (400 MHz, DMSO) δ: 6.68 (m, 1H), 6.75 (m, 2H), 7.35-7.45 (m,7H), 9.98 (s, 1H).

Step 2: 3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyltrifluoromethanesulfonate3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyltrifluoromethanesulfonate (2.5 g, 90%) was prepared from3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenol (1.5 g, 5.03mmol). The alcohol was dissolved in DCM (15 mL), cooled to 0° C. andtreated with triethylamine (0.66 g) for 10 minutes. Trifluoromethanesulphonyl chloride was then added at 0° C. and the mixture was warmed toRT and maintained at this temperature for 1.5 hours. The mixture thenwas poured into water (25 mL) and extracted with DCM (3×30 mL); thecombined organic extracts were then dried over Na₂SO₄ and concentratedin vacuo. The crude compound was used as such in the next step.

Mass spectroscopy: (ESI+ve) 431.0 [M+H]J, (ESI−ve) 429.0 [M−H]⁺.

General Procedure for Pd-Mediated Cross-Couplings of3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyltrifluoromethanesulfonate

3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyltrifluoromethanesulfonate (0.65 g, 1.51 mmol) was dissolved in DMF (10mL) and the resulting solution was treated sequentially with LiCl (0.21g) and a suitable organo-stannane or -boronic acid coupling partner(1.81 mmol). The resulting mixture was stirred at room temperature for5-10 minutes then treated with paladium(0) tetrakis triphenylphosphine(0.087 g, 0.075 mmol) at reflux (90° C.) for 4-5 hours. After this time,the mixture was poured into water (25 mL) and extracted with an organicsolvent such as DCM or ethyl acetate (3×30 mL). The combined organicextracts were then dried over Na₂SO₄, concentrated in vacuo and theisolated target compound was purified by gradient flash chromatography,eluting with ethyl acetate/hexane mixtures.

(i) 6-(3-Chloro-5-ethenylphenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Chloro-5-ethenylphenyl)-5-phenyl-1,2,4-triazin-3-amine (54 mg, 11%)was prepared from 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyltrifluoromethanesulfonate (0.65 g, 1.51 mmol and tri-n-butyl(vinyl) tin(0.57 g, 1.81 mmol) according to the general procedure for Example 4.

HPLC purity: 98.35% (248 nm)

Mass spectroscopy: (ESI+ve) 309.0 [M+H]⁺.

¹H NMR: (400 MHz, DMSO) δ: 5.27 (d, 1H), 5.72 (d, 1H), 6.62 (dd, 1H),7.23 (m, 1H), 7.44 (m, 6H), 7.51 (m, 1H), 7.57 (bs, 2H).

(ii) 6-(3-Chloro-5-cyclopropylphenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Chloro-5-cyclopropylphenyl)-5-phenyl-1,2,4-triazin-3-amine (20 mg,7%) was prepared from3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyltrifluoromethane-sulfonate (0.40 g, 0.93 mmol) andtri-n-butyl(cyclopropyl) tin (0.37 g, 1.11 mmol) according to thegeneral procedure for Example 4.

HPLC purity: 95.98% (227 nm)

Mass spectroscopy: (ESI+ve) 322.9 [M+H]⁺.

¹H NMR: (400 MHz, CDCl3) δ: 0.47 (m, 2H), 0.87 (m, 2H), 1.36 (m, 1H),5.58 (bs, 2H), 6.84 (s, 1H), 7.06 (s, 1H), 7.26 (s, 1H), 7.37 (m, 2H),7.45 (m, 3H).

Example 5: Other Synthetic Methods (i)6-(3,5-Dichlorophenyl)-5-(3-methylpiperidin-1-yl)-1,2,4-triazin-3-amine

Step 1: Selenium dioxide (30.0 g 270 mmol) was dissolved in dioxane (450mL) and warmed to 50° C. 3,5-Dichloroacetophenone (30.0 g, 158 mmol) wasadded at this temperature and the resulting mixture was refluxed for 4h. After completion of the reaction, the mixture was filtered throughcelite and concentrated in vacuo. (3,5-Dichlorophenyl)(oxo)acetic acidwas isolated and purified by column chromatography, eluting with ethylacetate/hexane mixtures (28 g, 80%).

Mass spectroscopy: (ESI−ve) 217 [M−H]⁻

Step 2: (3,5-Dichlorophenyl)(oxo)acetic acid (28.0 g 129.0 mmol) wasdissolved in ethanol (280 mL) and treated successively with a catalyticquantity of sulfuric acid and methyl hydrazinecarbimidothioate (20.5 g,193.5 mmol). The resulting mixture was stirred for 1 hr at 78° C. Aftercompletion of the reaction (TLC), the mixture was concentrated in vacuo,poured into water (150 mL), and extracted with DCM (3×250 ml). Thecombined organic extracts were then dried over Na₄SO₄, concentrated invacuo, and purified by gradient flash chromatography, affording6-(3,5-dichlorophenyl)-3-(methylthio)-1,2,4-triazin-5-ol (19 g, 46%).

Mass spectroscopy: (ESI+ve) 287.9 [M−H]+, (ESI−ve) 286.0 [M−H]⁺

¹H NMR: (400 MHz, DMSO) δ: 2.49 (s, 3H), 7.73 (m, 1H), 8.05 (d, 2H),14.32 (s, 1H).

Step 3: 6-(3,5-Dichlorophenyl)-3-(methylthio)-1,2,4-triazin-5-ol (2.0 g,6.96 mmol) was dissolved in 1,4-dioxane (20 mL) and cooled to 15° C. TEA(1.76 g, 17.4 mmol) was added drop wise to the solution, followed 5minutes later, by methanesulfonyl chloride (1.99 g, 17.42 mmol). Afterstirring at room temperature for 3 hours,6-(3,5-dichlorophenyl)-3-(methylsulfanyl)-1,2,4-triazin-5-ylmethanesulfonate was detected by LCMS and the crude mixture was useddirectly in the next step.

Mass spectroscopy: (ESI+ve) 366.9 [M−H]⁺

Step 4: A crude solution of6-(3,5-dichlorophenyl)-3-(methylsulfanyl)-1,2,4-triazin-5-ylmethanesulfonate (5.43 mmol) in dioxane (3 mL), was treated with K₂CO₃(1.0 g, 7.2 mmol) and 3-methyl piperidine (1.68 g, 16.9 mmol), and theresulting mixture was stirred at room temperature overnight. Aftercompletion of the reaction (TLC, ethyl acetate/hexane, 1:1), the mixturewas poured into water (25 mL) and extracted with DCM or ethyl acetate(3×25 ml). The combined organic extracts were then dried over Na₂SO₄,concentrated in vacuo and purified by flash chromatography, eluting with15% ethyl acetate in hexane to afford6-(3,5-dichlorophenyl)-5-(3-methylpiperidin-1-yl)-3-(methylsulfanyl)-1,2,4-triazine(0.8 g, 40%).

Mass spectroscopy: (ESI+ve) 369.0 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 0.67 (m, 3H), 1.07 (m, 2H), 1.35 (m, 1H),1.53 (m, 2H), 1.67 (m, 1H), 2.45 (s, 3H), 2.74 (m, 1H), 3.64 (m, 1H),3.76 (s, 1H), 7.60 (d, 2H), 7.64 (m, 1H).

Step 5: m-CPBA (0.654 g, 3.78 mmol) was added to a solution of a6-(3,5-dichlorophenyl)-5-(3-methylpiperidin-1-yl)-3-(methylsulfanyl)-1,2,4-triazine(0.4 g, 1.08 mmol) in DCM (5 mL) at −15° C. and the resulting mixturewas stirred at this temperature until the reaction was judged to becomplete by TLC (8 hrs). The reaction was then quenched with saturatedaqueous NaHCO₃ solution (15 ml) and extracted with ethyl acetate (3×15ml). The combined organic extracts were dried over Na₂SO₄ and evaporatedunder reduced pressure to afford crude6-(3,5-dichlorophenyl)-5-(3-methylpiperidin-1-yl)-3-(methylsulfonyl)-1,2,4-triazine(1.0 g, 91%) which was used without further purification.

Step 6: A6-(3,5-Dichlorophenyl)-5-(3-methylpiperidin-1-yl)-3-(methylsulfonyl)-1,2,4-triazine(0.25 g, 0.625 mmol) was dissolved in THF (5 mL) and the solution waspurged with anhydrous NH₃ gas for 1 hour. After completion of thereaction (TLC), the mixture was poured into water (15 mL) and extractedwith DCM or ethyl acetate (3×15 ml). The combined organic extracts weredried over Na₂SO₄, concentrated in vacuo and then treated with 1N HClsolution for 10 min and extracted with ethyl acetate. The separatedaqueous layer was neutralized with K₂CO₃ and extracted with ethylacetate (3×150 ml); the organic phases were then dried over Na₂SO₄ andpurified by gradient flash chromatography, affording6-(3,5-dichlorophenyl)-5-(3-methylpiperidin-1-yl)-1,2,4-triazin-3-amine(0.01 g, 1%).

HPLC purity: 88.07% (218 nm)

Mass spectroscopy: (ESI+ve) 338.9 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 0.90 (m, 1H), 1.16 (m, 2H), 1.42 (m, 2H),1.58 (s, 1H), 1.72 (m, 1H), 2.52 (m, 3H), 2.61 (m, 1H), 2.79 (m, 1H),7.64 (s, 2H), 7.76 (s, 1H), 7.64 (bs, 2H).

(ii) 6-(6-(Methylamino)pyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(6-(Methylamino)pyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine (49.5 mg,0.177 mmol, 71.4%) was prepared from5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)pyridin-2-yl(methyl)carbamate(vide supra), by BOC deprotection with trifluoroacetic acid (0.4 mL) indichloromethane (1.6 mL) for 1 hour at room temperature.

HPLC purity: 99.7% (254 nm) at 3.45 min

Mass spectroscopy: (ESI+ve) 279.8 [M+H]⁺

¹H NMR: (400 MHz, DMSO) δ: 2.74 (d, J 4.8, 3H), 6.36 (dd, J 8.7, 0.7,1H), 6.62-6.75 (m, 1H), 7.27 (s, 2H), 7.30 (dd, J 8.7, 2.4, 1H),7.36-7.47 (m, 5H), 7.90 (dd, J 2.4, 0.6, 1H).

(iii) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2,6-diiodophenol

4-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-phenol (vide supra; 140 mg,0.530 mmol) was reacted with AcOH (2 mL) and 1-iodopyrrolidine-2,5-dione(119 mg, 0.530 mmol). The mixture was stirred at room temperature for 1hour then concentrated in vacuo and purified by column chromatography(88 mg, 64%).

HPLC purity: 99% (254 nm) at 3.1 min

Mass spectroscopy: (ESI+ve) 517 [M+H]⁺; (ESI−ve) 515 [M−H]⁻

¹H NMR: (400 MHz, DMSO) δ: 7.35-7.50 (m, 7H), 7.64 (s, 2H), 9.69 (s,1H).

(iv) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-iodophenol

4-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-phenol (vide supra; 140 mg,0.530 mmol) was reacted with AcOH (2 mL) and 1-iodopyrrolidine-2,5-dione(119 mg, 0.530 mmol). The mixture was stirred at room temperature for 1hour then concentrated in vacuo and purified by column chromatography(35 mg, 32%).

HPLC purity: 99% (254 nm) at 2.7 min

Mass spectroscopy: (ESI+ve) 391 [M+H]⁺; (ESI−ve) 389 [M−H]⁻

¹H NMR: (400 MHz, DMSO) δ: 6.77 (d. J 8.4 Hz, 1H), 7.06 (dd, J 8.4, 2.2Hz, 1H), 7.28-7.47 (m, 7H), 7.68 (d, J 2.2 Hz, 1H), 10.51 (s, 1H).

(v)6-(3-Methoxy-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Methoxy-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazin-3-aminewas prepared from3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-(trifluoromethoxy)phenol (100mg, 0.287 mmol). The phenol was dissolved in THF (2 mL) and treated withiodomethane (17.87 μL, 0.287 mmol) at 0° C. After ˜15 minutes, themixture was then allowed to warm to r.t. slowly.

Solvent was removed in vacuo; water (2 ml) and DCM (2 ml) were added andthe layers were separated through a phase separator cartridge. Theorganic was concentrated to dryness in vacuo and purified by columnchromatography (33 mg, 32%).

HPLC purity: 100% (254 nm) at 4.82 min

Mass spectroscopy: (ESI+ve) 363 [M+H]⁺; (ESI−ve) 361 [M−H]⁻

¹H NMR: (400 MHz, DMSO) δ: 3.71 (s, 3H), 6.75-6.76 (m, 1H), 6.89-6.90(m, 1H), 7.00-7.01 (m, 1H), 7.32-7.48 (m, 5H), 7.53 (s, 2H)

(vi)N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamideStep 1: Preparation of N-(5-bromo-2-hydroxyphenyl)acetamide

2-Amino-4-bromophenol (1 g, 5.32 mmol) was dissolved in DCM (10 mL) andcooled to 10° C. Triethylamine (0.65 g, 6.38 mmol) was then addeddrop-wise and stirring continued for 5 minutes before acetyl chloride(0.54 g, 6.91 mmol) was added. The reaction mixture was monitored tocompletion by TLC (hexane/ethyl acetate, 7:3) then quenched by saturatedsodium bicarbonate solution (30 mL). The aqueous layer was extractedwith ethyl acetate (3×30 mL) and the combined organic phases were driedover Na₂SO₄ and concentrated in vacuo. The crude residue (0.57 g, 47%)was used in the next step without further purification.

TLC R_(f): 0.6 (hexane/ethyl acetate, 7:3)

Mass spectroscopy: (ESI+ve) 230.9 [M+H]⁺, (ESI−ve) 229.0 [M+H]⁺.

¹H NMR: (400 MHz, DMSO) δ: 2.07 (s, 3H), 6.78 (d, 1H), 7.04 (d, 1H),8.04 (d, 1H), 9.26 (s, 1H), 10.15 (s, 1H).

Step 2: Preparation of N-(5-bromo-2-methoxyphenyl)acetamide

N-(5-Bromo-2-hydroxyphenyl)acetamide (0.56 g, 2.43 mmol) was dissolvedin anhydrous DMF (7.0 mL) and treated with K₂CO₃ (0.85 g, 6.09 mmol).The resulting mixture was heated at 70° C. for 30 minutes then treatedwith methyl iodide (0.69 g, 4.87 mmol). After stirring for a further 16hours at 60° C., the reaction mixture was quenched with water (25 mL)and the aqueous layer was extracted with ethyl acetate (3×30 mL). Thecombined organic layers were dried over Na₂SO₄ and concentrated invacuo. The resulting residue (0.54 g, 92%) was used in the next stepwithout further purification.

Mass spectroscopy: (ESI+ve) 244.9 [M+H]J.

TLC R_(f): 0.8 (hexane/ethyl acetate, 7:3)

Step 3: Preparation ofN-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide

N-(5-Bromo-2-methoxyphenyl) acetamide (0.52 g, 2.13 mmol) was dissolvedin DME (10 mL) and treated with palladium(II) dibenzylidene acetone (65mg, 0.11 mmol), triphenyl phosphine (40 mg, 0.15 mmol),bis(pinacolato)diboron (0.65 g, 2.56 mmol) and potassium acetate (0.63g, 6.4 mmol). The resulting mixture was heated at 150° C. overnight thenquenched with water (30 mL). The aqueous layer was extracted with ethylacetate (3×30 mL) and the combined organic phases were dried over Na₂SO₄and concentrated in vacuo. The crude residue (1.08 g, 91%) was used inthe next step without further purification.

Mass spectroscopy: (ESI+ve) 292.1 [M+H]⁺.

TLC R_(f): 0.5 (hexane/ethyl acetate, 7:3)

Step 4: Preparation ofN-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide

N-[5-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide(0.170 g, 25%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine(0.5 g, 1.99 mmol) andN-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamideaccording to the general procedure of Example 1.

HPLC purity: 97.62% (283 nm)

Mass spectroscopy: (ESI+ve) 336.1 [M+H]⁺.

NMR: (400 MHz. DMSO) δ: 2.04 (s, 3H), 3.79 (s, 3H), 6.82 (d, 1H), 6.90(d, 1H), 7.33 (m, 4H), 7.39 (m, 3H), 8.13 (s, 1H), 9.13 (s, 1H).

(vii)N-[5-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-2-hydroxyphenyl]acetamide

N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-hydroxyphenyl]acetamide wasprepared by O-demethylation ofN-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide(0.05 g, 0.15 mmol: vide supra). The methyl ether was dissolved in DCM(5 mL), cooled to −78° C. and treated with borontribromide (5.25 mmol,1.32 g). The resulting mixture was gradually warmed to RT then stirredat this temperature for a further 16 hours. The mixture was poured intowater (15 mL) and extracted with DCM (3×15 mL). The combined organicextracts were dried over Na₂SO₄, concentrated in vacuum and purified bygradient flash chromatography, eluting with 30% ethyl acetate in hexaneto afford the target compound (0.30 g, 85%).

HPLC purity: 96.15% (219 nm)

Mass spectroscopy: (ESI+ve) 322.0 [M+H]⁺.

¹H NMR: (400 MHz, DMSO) δ: 2.05 (s, 3H), 6.71 (m, 2H), 7.43 (m, 5H),8.00 (m, 1H), 8.49 (bs, 2H), 9.26 (s, 1H), 10.26 (bs, 1H).

(viii)6-(2-Methyl-6-d₃-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine Step1: Preparation of 2,4,6-tri(d₃-methyl)cyclotriboroxane-pyridine complex

A solution of trimethyl borate (10.0 mL) in THF (100 mL) was cooledunder N₂ to −78° C. and a solution of methyl-d₃-magnesium iodide (50.0mL, 1 M in diethyl ether, 50.0 mmol) was added drop-wise over 1 hour.After stirring at −78° C. for a further 1.5 hours 1 M aqueous HCl (25mL) was added drop-wise over approximately 5 min and the mixture wasallowed to warm to room temperature. Brine (20 mL) was added and themixture was filtered through a short pad of celite, rinsing the celitepad with diethyl ether (50 mL). The phases were separated and theaqueous phase was extracted with diethyl ether (3×50 mL). The combinedorganic phases were washed with water (50 mL) and brine (50 mL) and thenconcentrated in vacuo to approximately 25 mL volume. Pyridine (10 mL)was added and the light yellow solution was stirred at ambienttemperature for 19.5 hours before concentration in vacuo to yield thetitle compound (1.39 g, crude) as a light-yellow semi-solid which wasused without purification.

LCMS: m/z 214.1 [M+H]⁺ (ESI+ve), 0.3 min (method A).

Step 2: Synthesis of6-(2-methyl-6-d_(s)-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine

A mixture of6-(2-chloro-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (70.4mg, 0.236 mmol), crude 2,4,6-tri(d₃)methylcyclotriboroxane-pyridinecomplex (504 mg, approximately 2.36 mmol), 1 M aqueous sodium carbonatesolution (0.59 mL, 0.59 mmol) andtetrakis(triphenylphosphine)palladium(0) (27.2 mg, 0.024 mmol) in1,4-dioxane (3 mL) and water (2 mL) in a sealed vial was heated in amicrowave reactor at 150° C. for 20 mins. After concentration in vacuo,DCM (10 mL) and water (10 mL) were added and the phases were separated.The aqueous phase was extracted with DCM (2×5 mL) and the combinedorganic phases concentrated in vacuo. Purification by gradient flashchromatography (SiO₂, 5 to 40% solvent A in B. Solvent A: CH₂Cl₂,solvent B: 7N NH₃ in MeOH/MeOH/CH₂Cl₂ 5:5:90) yielded the title compoundas a yellow solid (30.5 mg, 46%).

LCMS m/z 281.1 (M+H)⁺ (ES⁺) at 2.26 min, 100% (method C).

NMR (400 MHz, CDCl₃) δ: 2.47 (s, 3H), 5.44 (s, 2H), 7.02 (s, 2H),7.33-7.39 (m, 2H), 7.43-7.49 (m, 3H).

(ix)1-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-3,5-dimethylpyridin-4(1H)-oneStep 1: Preparation of1-(3,5-dimethylpyridin-4-yl)-3,5-dimethylpyridinium chloride

3,5-lutidine (1.0 g, 9.3 mmol) was added to SOCl₂ (2.0 mL, 27.9 mmol) at−10° C. The resulting mixture was heated to 120′C and was stirred for afurther two to three hours. The reaction was monitored to completion byTLC (ethyl acetate/hexane, 1:1) then precipitated with ethyl acetate.The desired product was collected by filtration and used in the nextstep without further purification (1.79 g, 90%).

Mass: (ESI+ve) 214.1 [M+H]r

TLC R_(f): 0.05 (methanol/chloroform, 3:7).

Step 2: Preparation of 3,5-dimethylpyridin-4-ol

1-(3,5-dimethylpyridin-4-yl)-3,5-dimethylpyridinium chloride (1.0 g, 4.7mmol) and anhydrous H₃PO₃ (0.97 g, 11.7 mmol) were heated, as a neatmixture, to 150-160° C. in a sealed tube for 8 hours with TLC monitoring(methanol/chloroform 5:5). Upon completion of the reaction, the mixturewas diluted with ethanol and acetone (1:1, 50 mL), filtered andconcentrated under vacuum. The product was purified employing Dowex 50resin.

Mass: (ESI+ve) 124.0 [M+H]⁺

TLC R_(f): 0.38 (methanol/chloroform, 2:8).

Step 3: Preparation of1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3,5-dimethylpyridin-4(1H)-one

1-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-3,5-dimethylpyridin-4(1H)-one(40 mg, 5%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine(0.70 g, 2.7 mmol), 3,5-dimethylpyridin-4-ol (0.45 g, 3.7 mmol) andK₂CO₃ (0.93 g, 6.7 mmol) according to the general procedure of Example3.

HPLC purity: 92.33% (286 nm)

Mass spectroscopy: (ESI+ve) 294.1 [M+H]⁺

¹H NMR: (400 MHz, CDCl3) δ: 1.77 (s, 6H), 7.44 (m, 5H), 7.66 (s, 2H),7.74 (bs, 2H).

(x)6-[2-(Azetidin-1-yl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine

6-[2-(Azetidin-1-yl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-aminewas prepared from5-phenyl-6-(2-chloro-6-methyl-pyridin-4-yl)-1,2,4-triazin-3-amine (100mg, 0.34 mmol) and azetidine (96 mg, 0.11 ml, 1.69 mmol) according tothe general procedure for Preparation 4a.

LCMS: (ES⁺) 319.1 (M+H)⁺ at 4.02 min, 99% (method C).

¹H NMR: (400 MHz, DMSO) δ: 2.22 (s, 3H), 2.22-2.28 (m, 2H), 3.76 (t, J7.3, 4H), 5.99 (s, 1H), 6.47 (s, 1H), 7.39-7.50 (m, 5H), 7.52 (bs, 2H).

(xi)6-[2-(azetidin-1-yl)-6-methylpyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine

6-[2-(azetidin-1-yl)-6-methylpyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine(6.0 mg, 4%) was prepared from5-(4-fluorophenyl)-6-(2-chloro-6-methyl-pyridin-4-yl)-1,2,4-triazin-3-amine(150 mg, 0.48 mmol) and azetidine (136 mg, 0.16 ml, 2.38 mmol) accordingto the general procedure for Preparation 4a.

LCMS: (ES⁺) 337.1 (M+H)⁺ at 4.18 min, 97% (method C).

¹H NMR: (400 MHz, DMSO) δ: 2.23 (s, 3H), 2.24-2.30 (m, 2H), 3.79 (t, J7.6, 4H), 6.52 (s, 1H), 6.86 (s, 1H), 7.24-7.29 (m, 2H), 7.48-7.50 (m,2H), 7.55 (bs, 2H).

(xii)6-[2-(Azetidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine

6-[2-(Azetidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine(20.0 mg, 19%) was prepared from5-phenyl-6-(2-chloro-6-trifluoromethyl-pyridin-4-yl)-1,2,4-triazin-3-amine(100 mg, 0.28 mmol) and azetidine according to the general procedure forPreparation 4a.

LCMS: (ES⁺) 373.0 (M+H)⁺ at 4.52 min, 99% (method C).

¹H NMR: (400 MHz, DMSO) δ: 2.27-2.35 (m, 2H), 3.89 (t, J 7.5, 4H), 6.03(s, 1H), 6.46 (s, 1H), 7.41-7.53 (m, 5H), 7.69 (br. s, 2H).

Example 6

The compounds of Examples 1 to 5 were found to possess activity inbiological tests described above. Biological activity determined by TestA includes IC₅₀ and pKi values for human A_(2a) and A₁ receptors, andthe compounds of Examples 1 to 5 were found to possess pKi values inexcess of 5 (or 6) vs. at least one of these receptors (for example asillustrated for certain compounds in the table below).

Example no. pKi A2a pKi A1 1(vi) 7.29 7.25 1(ix) 7.70 7.81 1(xiii) 8.407.36 1(xv) 7.11 8.45 1(xviii) 6.75 6.91 1(xxiv) 6.97 8.03 1(xxx) 6.30 ND1(xxxv) 7.19 8.20 1(xli) 8.68 7.83 1(xlii) 8.86 9.84 1(xliii) 7.74 8.541(li) 8.66 6.87 1(lvi) 8.22 7.33 1(lxxii) 6.99 8.52 1(lxxvii) 8.11 7.291(lxxix) 7.45 9.35 1(lxxx) 6.61 6.01 1(xc) 8.07 7.26 1(xcv) 7.86 6.671(cxxxiv) 5.62 7.62 1(cxlvi) 6.31 7.40 1(cliv) 7.56 6.77 1(clviii) 7.986.96 1(clix) 7.81 7.07 1(clxix) 8.40 6.99 1(clxxiv) 8.07 6.89 1(clxxvi)8.03 6.93 1(clxxix) 8.62 7.52 1(clxxx) 8.90 7.76 1(clxxxi) 8.71 7.171(cxci) 8.26 7.36 1(cxciii) 8.34 6.93 1(cciv) 7.21 5.97 1(ccix) 8.597.60 1(ccxi) 7.71 8.74 1(ccxii) 8.66 7.68 1(ccxiii) 7.51 7.12 1(ccxviii)6.58 5.25 2(iii) 7.31 5.37 2(iv) 7.79 <5 2(vi) 7.39 <5 2(xxii) 5.07 6.712(xxv) 5.53 7.49 3(i) 7.17 <5 3(v) 5.96 ND 3(xvi) 7.41 7.15 3(xxi) 6.228.07 3(xxiv) 7.39 8.46 3(xxxii) 5.82 7.00 4(ii) 7.89 7.43 5(vii) 6.738.69 5(viii) 7.91 7.26 5(ix) 7.77 7.62 5(x) 8.52 8.05 5(xi) 7.76 6.90

Example 7

The compounds of Example 1(vi) and Example 1 (xliii) (dose of 2-10 mg/kgor 0.3-3 mg/kg, p.o., respectively; 120 min pre-test time) were found toreverse cataleptic behaviour in rats pre-treated with haloperidol in adose-dependent manner with an ED₅₀ of 9.8 and 0.27 mg/kg (p.o.),respectively, using the procedure described in Test B above. In asimilar manner, the compounds of Examples 1(xiii), 1(li), 1(lvi),1(lxxvii), 1(xc), 1(xcv), 1(cliv), 1(clviii), 1(clix), 1(ccix), 1(cxci),1(cxciii), 1(clxix), 1(clxxix), 1(clxxxiv), 1(ccxii) and 5(x) were foundto reverse cataleptic behavior in rats pre-treated with haloperidol in astatistically significant manner at a dose of 1 mg/kg (p.o.) (with a 120min pre-test time, according to Test B above.

Abbreviations

m-CPBA=m-chloroperoxybenzoic acid

bmim=1-butyl-3-methylimidazolium

DCM=dichloromethane

DME=dimethoxyethane

DMF=dimethylformamide

DMSO=dimethylsulfoxide

ESI=electro spray ionisation

EtOAc=Ethyl acetate

FT=fourier transform

HPLC=high performance liquid chromatography

IR=infra-red

LC=liquid chromatography

MS=mass spectrometry

NMP=N-methyl pyrrolidinone

NMR=nuclear magnetic resonance

rt=room temperature

THF=tetrahydrofuran

TLC=thin layer chromatography

Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal,secondary, iso, and tertiary.

The invention claimed is:
 1. A method of treatment of cancer, comprisingadministering an effective amount of6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine,or a pharmaceutically acceptable salt or solvate, to a patient in needof such treatment, wherein the cancer is selected from the groupconsisting of prostate cancer, rectal cancer, renal cancer, ovariancancer, endometrial cancer, thyroid cancer, pancreatic cancer, breastcancer, colon cancer, bladder cancer, brain cancer, glia cancer,melanoma cancer, pineal gland cancer, and lung cancer.
 2. The method asclaimed in claim 1, wherein the cancer is selected from the groupconsisting of rectal cancer, pancreatic cancer, colon cancer, braincancer, glia cancer, and lung cancer.
 3. A compound, wherein thecompound is6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine,or a pharmaceutically acceptable salt or solvate.